Novel tricyclic compounds useful for the treatment of inflammatory and allergic disorders:process for their preparation and pharmaceutical compositions containing them

ABSTRACT

The present invention relates to novel tricyclic compounds useful for the treatment of inflammatory conditions, diseases of the central nervous and insulin resistant diabetes.

FIELD OF THE INVENTION

The present invention relates to novel tricyclic compounds, theiranalogs, their tautomers, their regioisomers, their stereoisomers, theirenantiomers, their diastereomers, their polymorphs, theirpharmaceutically acceptable salts, their N-oxides, theirpharmaceutically acceptable solvates and their pharmaceuticalcompositions containing them. The present invention more particularlyrelates to novel Phosphodiesterase type 4 (PDE4) inhibitors of theformula (1A), their analogs, their tautomers, their enantiomers, theirdiastereomers, their regioisomers, their stereoisomers, theirpolymorphs, their pharmaceutically acceptable salts, their N-oxides,their pharmaceutically acceptable solvates and the pharmaceuticalcompositions containing them.

The novel tricyclic compounds are of general formula (IA)

wherein:

-   -   R¹, R² and R³ may be same or different and are independently        selected from the groups consisting of hydrogen, substituted or        unsubstituted alkyl, substituted or unsubstituted alkenyl,        substituted or unsubstituted alkynyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        cycloalkylakyl, substituted or unsubstituted cycloalkenyl,        substituted or unsubstituted aryl, substituted or unsubstituted        arylalkyl, substituted or unsubstituted heteroaryl, substituted        or unsubstituted heterocyclic group, substituted or        unsubstituted heterocyclylalkyl, substituted or unsubstituted        heteroarylalkyl, —C(O)—-R¹,—C(O)O—R¹, —C(O)NR¹R¹, —S(O)_(m)—R¹,        S(O)_(m)—NR¹R¹, nitro, —OH, cyano, amino, formyl, acetyl,        halogen, —OR¹, —SR¹, protecting groups or when two R²        substitutents are ortho to each other, may be joined to a form a        saturated or unsaturated cyclic ring, which may optionally        include up to two heteroatoms selected from O, NR¹ or S;    -   wherein P represents oxygen or sulfur,    -   wherein n represents 0-4;    -   Ar is substituted or unsubstituted aryl, substituted or        unsubstituted arylalkyl, substituted or unsubstituted        heterocyclic ring or substituted or unsubstituted heteroaryl        ring,    -   Preferably Ar is optionally substituted phenyl, optionally        substituted benzyl, optionally substituted pyramidine,        optionally substituted pyridyl selected from 4-pyridyl,        3-pyridyl and 2-pyridyl or optionally substituted        pyridyl-N-oxide selected from 4-pyridyl-N-oxide,        3-pyridyl-N-oxide and 2-pyridyl-N-oxide in which optional        substituents (one or more) may be same or different and are        independently selected from the groups consisting of hydrogen,        hydroxyl, halogen, cyano, nitro, carboxyl, trifluoroalkyl,        substituted or unsubstituted alkyl, substituted or unsubstituted        alkoxy, substituted or unsubstituted alkoxycarbonyl, substituted        or unsubstituted alkylcarbonyl, substituted or unsubstituted        alkylcarbonyloxy, substituted or unsubstituted amino or mono or        di substituted or unsubstituted alkylamino    -   X is oxygen, S(O)_(m) or NR⁵;    -   R⁵ represents hydrogen, substituted or unsubstituted alkyl,        substituted or unsubstituted alkenyl, substituted or        unsubstitued alkynyl, substituted or unsubstituted cycloalkyl,        substituted or unsubstituted cycloalkylakyl, substituted or        unsubstituted cycloalkenyl, substituted or unsubstituted aryl,        substituted or unsubstituted arylalkyl, substituted or        unsubstituted heteroaryl, substituted or unsubstituted        heterocyclic ring, substituted or unsubstituted        heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl,        —C(O)—R¹, —C(O)O—R¹, —C(O)NR¹R¹, —S(O)_(m)—R¹, —S(O)_(m)—NR¹R¹,        nitro, —OH, cyano, amino, formyl, acetyl, halogen, —OR¹, —SR¹        and protecting groups    -   Wherein m is 0, 1 or 2;    -   Y is —C(O)NR⁴, —NR⁴SO₂, —SO₂NR⁴or —NR⁴C(O);    -   R⁴ is hydrogen, substituted or unsubstituted alkyl, hydroxyl,        —OR¹, —COOR¹, substituted or unsubstituted aryl) substituted or        unsubstituted heterocyclic ring;    -   and their analogs, their tautomers, their regioisomers, their        stereoisomers, their enantiomers, their diastereomers, their        polymorphs, their pharmaceutically acceptable salts, their        N-oxides, their pharmaceutically acceptable solvates and their        pharmaceutical compositions containing them or a pharmaceutical        acceptable salts thereof.

More particularly, the present invention provides a compound of formula(1)

wherein:

-   -   R¹, R² and R³ may be same or different and are independently        selected from the groups consisting of hydrogen, substituted or        unsubstituted alkyl, substituted or unsubstituted alkenyl,        substituted or unsubstitued alkynyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        cycloalkylakyl, substituted or unsubstituted cycloalkenyl,        substituted or unsubstituted aryl, substituted or unsubstituted        arylalkyl, substituted or unsubstituted heteroaryl substituted        or unsubstituted heterocyclic group, substituted or        unsubstituted heterocyclylalkyl, substituted or unsubstituted        heteroarylalkyl, —C(O)-R¹, —C(O)O—R¹, —C(O)NR¹R¹, —S(O)_(m)—R¹,        —S(O)_(m)—NR¹R¹, nitro, —OH, cyano, amino, formyl, acetyl,        halogen, —OR¹, —SR¹, protecting groups or when two R²        substitutents ortho to each other, may be joined to a form a        saturated or unsaturated cyclic ring, which may optionally        include up to two heteroatoms selected from O, NR¹ or S;    -   wherein P represents oxygen or sulfur;    -   wherein n represents 0-4;    -   Ar is substituted or unsubstituted aryl, substituted or        unsubstituted arylalkyl, substituted or unsubstituted        heterocyclic ring or substituted or unsubstituted heteroaryl        ring;    -   Preferably Ar is optionally substituted phenyl, optionally        substituted benzyl, optionally substituted pyramidine,        optionally substituted pyridyl selected from 4-pyridyl,        3-pyridyl and 2-pyridyl or optionally substituted        pyridyl-N-oxide selected from 4-pyridyl-N-Oxide,        3-pyridyl-N-Oxide and 2-pyridyl-N-Oxide in which optional        substituents (one or more) may be same or different and are        independently selected from the groups consisting of hydrogen,        hydroxyl, halogen, cyano, nitro, carboxyl, trifluoroalkyl,        substituted or unsubstituted alkyl, substituted or unsubstituted        alkoxy, substituted or unsubstituted alkoxycarbonyl, substituted        or unsubstituted alkylcarbonyl, substituted or unsubstituted        alkylcarbonyloxy, substituted or unsubstituted amino or mono or        di substituted or unsubstituted alkylamino    -   X is oxygen, S(O)_(m) or NR⁵;    -   R⁵ represents hydrogen, substituted or unsubstituted alkyl,        substituted or unsubstituted alkenyl, substituted or        unsubstitued alkynyl, substituted or unsubstituted cycloalkyl,        substituted or unsubstituted cycloalkylakyl, substituted or        unsubstituted cycloalkenyl, substituted or unsubstituted aryl,        substituted or unsubstituted arylalkyl, substituted or        unsubstituted heteroaryl, substituted or unsubstituted        heterocyclic group, substituted or unsubstituted        heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl,        —C(O)—R¹, —C(O)O—R¹, —C(O)NR¹R¹, —S(O)_(m)—R¹, —S(O)_(m)—NR¹R¹,        nitro, —OH, cyano, amino, formyl, acetyl, halogen, —OR¹, —SR¹        and protecting groups    -   Wherein m is 0, 1 or 2;    -   Y is —C(O)NR⁴, —NR⁴SO₂, —SO₂NR or —NR⁴C(O);    -   R⁴ is hydrogen, substituted or unsubstituted alkyl, hydroxyl,        —OR¹, —COOR¹, substituted or unsubstituted aryl, substituted or        unsubstituted heterocyclic ring;    -   and their analogs, their tautomers, their regioisomers, their        stereoisomers, their enantiomers, their diastreomers, their        polymorphs, their pharmaceutically acceptable salts, their        N-oxides, their pharmaceutically acceptable solvates and their        pharmaceutical compositions containing them or a pharmaceutical        acceptable salts thereof

The present invention also relates to a process for the preparation ofthe above said novel heterocyclic compounds of formula 1 as definedabove. The compounds of general formula (1) more particularly, downregulate or inhibit the production of TNF-α as they are PDE4 inhibitorsand therefore are useful in the treatment of variety of allergic andinflammatory diseases including asthma, chronic bronchitis, atopicdermatitis, urticaria, allergic rhinitis, allergic conjunctivitis,vernal conjuctivitis, eosinophilic granuloma, psoriasis, rheumatoidarthritis, septic shock, ulcerative colitis, Crohn's disease,reperfusion injury of the myocardium and reperfusion injury of thebrain, chronic glomerulonephritis, endotoxic shock and adult respiratorydistress syndrome. The compounds of the present invention areparticularly useful for the treatment of asthma.

BACKGROUND OF THE INVENTION

Airway inflammation characterizes a number of severe lung diseasesincluding asthma and chronic obstructive pulmonary disease (COPD).Events leading to airway obstruction include edema of airway walls,infiltration of inflammatory cells into the lung, production of variousinflammatory mediators and increased mucous production. The airways ofasthmatic patients are infiltrated by inflammatory leukocytes, of whichthe eosinophil is the most prominent component The magnitude ofasthmatic reactions is correlated with the number of eosinophils presentin lungs.

The accumulation of eosinophils is found dramatically in the lungs ofasthmatic patients although there are very few in the lungs of a normalindividual. They are capable of lysing and activating cells anddestroying tissues. When activated, they synthesize and releaseinflammatory cytokines such as IL-1, IL-3, TNF-α and inflammatorymediators such as PAF, LTD4 and related oxygen species that can produceedema and broncho-constriction. Tumor necrosis factor (TNF-α) was alsoknown to be involved in the pathogenesis of a number of autoimmune andinflammatory diseases. Consequently, manipulation of the cytokinesignaling or biosynthetic pathways associated with these proteins mayprovide therapeutic benefit in those disease states. It has been welldemonstrated that TNF-α production in pro-inflammatory cells becomesattenuated by an elevation of intracellular cyclic adenosine3′,5′-monophosphate (cAMP). This second messenger is regulated by thephosphodiesterase (PDE) family of enzymes. The phosphodiesterase enzymesplay an integral role in cell signaling mechanisms by hydrolyzing cAMPand cGP to their inactive 5′ forms. Inhibition of PDE enzymes thusresults in an elevation of cAMP and /or cGP levels and altersintracellular responses to extra cellular signals by affecting theprocesses mediated by cyclic nucleotides. Since eosinophilis arebelieved to be a critical proinflammatory target for asthma,identification of the expression of the PDE 4 gene family in eosinophilsled to PDE 4 as potential therapeutic target for asthma [Rogers, D. F.,Giembycz, M. A., Trends Pharmacol, Sci., 19, 160-164(1998); Barnes, P.J., Trends Pharmacol. Sci., 19, 415-423 (1998) herein incorporated byreference in their entirety].

The mammalian cyclic nucleotide phosphodiesterases (PDEs) are classifiedinto ten families on the basis of their amino acid sequences and/or DNAsequence, substrate specificity and sensitivity to pharmacologicalagents [Soderling, S. H., Bayuga, S. J., and Beavo, J. A., Proc. Natl.Acad. Sci., USA, 96, 7071-7076 (1999); Fujishige, K, Kotera, J.,Michibata, H., Yuasa, K., Takebayashi, Si, Okamura, K and Omori, K, J.Biol. Chem., 274, 18438-18445 (1999) herein incorporated by reference intheir entirety]. Many cell types express more than one PDE anddistribution of isoenzymes between the cells varies markedly. Thereforedevelopment of highly isoenzyme selective PDE inhibitors provides aunique opportunity for selective manipulation of variouspathophysiological processes.

Phosphodiesterase type 4 (PDE4) is an enzyme which regulates activitiesin cells which lead to inflammation in the lungs. PDE4, a cAMP-specificand Ca⁺²-independent enzyme, is a key isozyme in the hydrolysis of cAMPin mast cells, basophils, eosinophils, monocytes and lymphocytes. Theassociation between cAMP elevation in inflammatory cells with airwaysmooth muscle relaxation and inhibition of mediator release has led towidespread interest in the design of PDE4 inhibitors[Trophy, T. J., Am.J. Respir. Crit. Care Med., 157, 351-370 (1998) herein incorporated byreference in their entirety]. Excessive or unregulated TNF-α productionhas been implicated in mediating or exacerbating a number of undesirablephysiological conditions such as diseases including osteoarthritis, andother arthritic conditions; septic shock, endotoxic shock, respiratorydistress syndrome and bone resorption diseases since TNF-α alsoparticipates in the onset and progress of autoimmune diseases, PDE4inhibitors may find utility as therapeutic agents for rheumatoidarthritis, multiple sclerosis and Crohn's disease. [Nature Medicine, 1,211-214 (1995) and ibid., 244-248 herein incorporated by reference intheir entirety].

Strong interest in drugs capable of selective inhibition of PDE 4 is dueto several factors. Tissue distribution of PDE-4 suggests thatpathologies related to the central nervous and immune systems could betreated with selective PDE-4 inhibitors. In addition, the increase inintracellular cAMP concentration, the obvious biochemical consequence ofPDE-4 inhibition, has been well characterized in immuno-competent cellswhere it acts as a deactivating signal.

Recently the PDE family has grown to include four subtypes-PDE4A toPDE4D, each encoded by a distinct gene (British Journal of Pharmacology;1999; v.128; p. 1393-1398), herein incorporated by reference in itsentirety.

It has been demonstrated that increasing cAMP levels within these cellsresults in suppression of cell activation, which in turn inhibits theproduction and release of pro-inflammatory cytokines such as TNF-α.Since eosinophilis are believed to be a critical pro-inflammatory targetfor asthma, identification of the expression of the PDE-4 gene family ineosinophils led to the PDE-4 as a potential therapeutic target forasthma.

The usefulness of several PDE-4 inhibitors, unfortunately, is limiteddue to their undesirable side effect profile which include nausea andemesis (due to action on PDE-4 in the central nervous system) andgastric acid secretion due to action on PDE-4 in parietal cells in thegut Barnette, M. S., Grous, M., Cieslinsky, L. B., Burman, M.,Christensen, S. B., Trophy, T. J., J. Pharmacol. Exp. Ther.,273,1396-1402 (1995) herein incorporated by reference in their entirety.One of the earliest PDE-4 inhibitors, Rolipram™, was withdrawn fromclinical development because of its severe unacceptable side effectprofile. Zeller E. et. al., Pharmacopsychiatr., 17, 188-190 (1984)herein incorporated by reference in its entirety. The cause of severeside effects of several PDE-4 inhibitor molecules in human clinicaltrials has recently become apparent.

There exist two binding sites on mammalian PDE-4at which inhibitormolecules may bind. Also PDE-4 exists in two distinct forms whichrepresent different conformations. They are designated as High affinityRolipram binding site PDE-4H and Low affinity Rolipram binding sitePDE-4L [Jacobitz, S., McLaughlin, M. M., Livi, G. P., Burman, M.,Trophy, T. J., Mol. Pharmaco., 50, 891-899 (1996) herein incorporated byreference in their entirety]. It was shown that certain side effects(vomiting and gastric acid secretion) are associated with inhibition ofPDE-4H whereas some beneficial actions are associated with PDE-4Linhibition. It was also found that human recombinant PDE-4 exists id 4isoforms A, B, C and D [Muller, T., Engels, P., Fozard, J. R., TrendsPharmacol. Sci., 17 294-298 (1996) herein incorporated by reference inits entirety]. Accordingly, compounds displaying more PDE-4D isoenzymeselectivity over the A, B or C are found to have fewer side effects thanRolipram [Hughes. B et.al., Br. J. Pharmacol. 1996, 118, 1183-1191herein incorporated by reference in their entirety]. Therefore,selective inhibitors of PDE-4 isozymes would have therapeutic effects ininflammatory diseases such as asthma and other respiratory diseases.

Although several research groups all over the world are working to findhighly selective PDE-4 isozyme inhibitors, so far success has beenlimited. Various compounds have shown PDE-4 inhibition.

SmithKline Beecham's “Ariflo” which has the formula A, Byk Gulden'sRoflumilast which has the formula D and Bayer's Bay-19-8004 which hasthe formula E have reached advanced stage of human clinical trials.Other compounds which have shown potent PDE-4 inhibitory activityinclude Celltech's CDP-840 of the formula B, Schering Plough's D-4418 ofthe formula C, Pfizer's 5CP-220,629 which has the formula F, ParkeDavis's PD-168787 which has the formula G and Wyeth's Filaminast whichhas the formula H. However, recently due to efficacy and side effectsproblems, Ariflo, CDP-840 and Bay-19-8004 were discontinued fromclinical trials as a treatment for asthma. Other compounds of theformulae C and F are presently undergoing phase-1 clinical trials.

U.S. Pat. No. 4,933,351 describes Benzofuran 2-carboxy amides useful asinhibitors of leukoriene biosynthesis, a compound of the formula I andacceptable pharmaceutical carrier:

wherein:

-   -   Z is a bond, CR₁₄═CR,₅;    -   X is O, S, SO or SO₂;    -   R₂ is H, OH, C₁ to C₂₀ alkoxy, including straight chain or        branched chain, cycloalkyl, bicycloalkyl, tricycloalkyl or        tetracycloalkyl;    -   Ar₁—C₁ to C₃ alkoxy;    -   NR₈Ar₁, wherein R₈ and Ar₁ can optionally be joined to form a        heterocyclic ring having 5 to 8 atoms;    -   —NR₈Het;    -   —N(R₈)CH₂Ar₁    -   —N(R₁₃)—N(R₁₃)₂ wherein R₁₃ is independently hydrogen, R₈,        R₉,Ar₁ or Het:    -   —NH—CH═C(Ar₁)₂;    -   —O(CH₂)_(n)NR₈R₉ wherein N is 2 to 4;    -   -Z-Ar₁;        lower acyloxy-lower alkoxy    -   —CH₂OH;    -   —(CH₂)_(n)Ar₁ wherein in n is 0 to 3;    -   —(CH₂)_(n)COOR₆ wherein n is 0 to 6;    -   C₁ to C₂₀ alkyl; Ar₁; Het; (CH₂)_(n)NR₈R₉    -   Wherein n is 1 to 3; or Het;    -   and R₁, R₃ R₄, T and V are independently selected from        -   1. hydrogen;        -   2. alkyl having 1 to 6 carbon atoms;        -   3. alkenyl having 2 to 6 carbon atoms;        -   4. —(CH₂)_(n)M wherein n is 0 to 6 except when X is S and M            is OR₅, in which n is 1 to 6 and M is    -   a) —OR₅;    -   b) halogen;    -   c) —CF₃;    -   d)—SR₅;    -   e) Ar₁;    -   f) —COOR₆;        Wherein R₁₂ is H, C₁ to C₆ alkyl, or Ar₁;    -   h) tetrazole;    -   n)        -   —NHSO₂R₁₀ Wherein R₁₀ is OH, C₁ to C₆ alkyl, CF₃, C₁ to C₆            alkoxy, or Ar;    -   p) —SOR₅    -   q) —CONR₈R₉;    -   r) —SO₂NR₈R₉;    -   s) —SO₂R₅;    -   t) —NO₂; or    -   u) —CN    -   or any two of R₃,R₄,T and V may be joined to form a saturated        ring having 5 to 6 ring atoms, said ring atoms comprising 0,1 or        2 atoms selected from oxygen and sulfur, the remaining ring        atoms been carbon;    -   each R₅ is independently H, C₁ to C₆ alkyl, benzene, Ar₁,        perfluro-C₁ to C₄ allyl, CH₂-R₁₁ is C₁ to C₅        alkyldimethylamino,hydroxyl-C₂ to C₅ alkyl, CH₂COOR₆, or        CH₂CO—R₇;    -   each R₆ is independently H, or C₁ to C₆ alkyl;    -   each R₇ is independently C₁ to C₆ alkyl, benzyl, Ar₁, NR₈R₉,        NHAr₁ or O—C₁ to C₄ alkyl;    -   each R₈ and R₉ is independently H or C₁ to C₄ alkyl, or R₈ and        R₉ may be joined through the N to which they are attached to        form a heterocycloalkyl ring having 5 to 8 ring atoms;    -   each Het is independently an aromatic heterocyclic ring having 5        to 6 ring atoms, one or more of which is selected from N, O and        S;    -   each Ar₁ is independently 1- or 2-naphtyl, phenyl or mono- or        disubstituted phenyl, wherein the substituents on phenyl are        independently selected from C₁ to C₃ alkyl, I Br, Cl, F, COOR₆,        (CH₂)_(n)—NR₈R₉ wherein n is 0 to 2, methylenedioxy, C₁ to C₃        alkoxy, OH, CN,NO₂, CF₃, C₁ to C₄ acyl, NR₈R₉, S—C₁ to C₆ alkyl,        SO—C₁ to C₆ alkyl, and SO ₂—C₁ to C₆ alkyl; and R₁₄ and R₁₅ are        each independently H, C₁ to C₆ alkyl; or a pharmaceutically        acceptable salts thereof

WO 94/08995 describes heterocyclic condensed benzoic acid derivatives as5-HT4 receptor antagonists of formula (I-1) or a pharmaceuticallyaccepted salts thereof:

Wherein X is O, or S;

-   -   R₁ is hydrogen, amino, halo, C₁₋₆alkyl, hydroxyl or C₁₋₆alkoxy;    -   R₂ is hydrogen, halo, C₁₋₆alkyl, C₁₋₆alkoxy, nitro, amino, or        C₁₋₆alkylthio;    -   R₃ is hydrogen, halo, C₁₋₆alkyl, C₁₋₆alkoxy, or amino; and    -   R₄ is hydrogen or C₁₋₆alkyl.

WO 94/08995 also describes

Wherein

-   -   X is O or S    -   A represent a single bond, —CH₂— or CO or A is        (CH₂)_(a)-E-CH₂)_(b) where one of a and b is 0 and the other is        0 or 1 and E is O,S or NH;    -   R₁ is hydrogen, amino, halo, C₁₋₆alkyl, hydroxyl or C₁₋₆alkoxy;    -   R₂ is hydrogen, halo, C₁₋₆alkyl, C₁₋₆alkoxy, nitro, amino, or        C₁₋₆alkylthio;    -   R₃ is hydrogen, halo, C₁₋₆alkyl, C₁₋₆alkoxy, or amino; and    -   R₄ is hydrogen or C₁₋₆alkyl.

WO 94/08995 also describes

Wherein

-   -   X is O or S    -   A represent a single bond, —CH₂— or CO or A is        (CH₂)_(a)-E-(CH₂)_(b) where one of a and b is 0 and the other is        0 or 1 and E is O,S or NH;    -   f and g are both hydrogen or together are a bond;    -   R₁ is hydrogen, amino, halo, C₁₋₆alkyl, hydroxyl or C₁₋₄alkoxy;    -   R₂ is hydrogen, halo, C₁₋₆alkyl, C₁₋₄alkoxy, nitro, amino, or        C₁₋₆alkylthio;    -   R₃ is hydrogen, halo, C₁₋₆alkyl, C₁₋₆alkoxy, or amino; and    -   R₄ is hydrogen or C₁₋₆alkyl.

WO 94/08995 also describes

Wherein

-   -   X is O or S;    -   R₁ is hydrogen, amino, halo, C₁₋₆alkyl, hydroxyl or C₁₋₆alkoxy;    -   R₂ is hydrogen, halo, C₁₋₆alkyl, C₁₋₆alkoxy, nitro, amino, or        C₁₋₆alkylthio;    -   R₃ is hydrogen, halo, C₁₋₆alkyl, C₁₋₆alkoxy, or amino; and    -   R₄ ¹ and R₄ ¹¹ are independently hydrogen or C₁₋₆alkyl.

In formulae (I-1) to (I-4) inclusive:

-   -   Y is O or NH;    -   Z is of sub-formula (a), (b) or (c):        Wherein n¹ is 0,1,2,3 or 4; n² is 0,1,2,3 or 4; n³ is 2,3,4 or        5;    -   q is 0,1,2 or 3; p is 0,1 or 2; m is 0,1 or 2;    -   R₅ is hydrogen, C₁₋₁₂ alkyl, aralkyl or R₅ is (CH₂)_(z)-R₁₀        wherein z is 2 or 3 and R₁₀ is selected from cyano, hydroxyl,        C₁₋₆alkoxy, phenoxy, C(O)C₁₋₆alkyl, COC₆H₅, —CONR₁₁R₁₂,        NR₁₁COR₁₂, SO₂NR₁₁R₁₂ or NR₁₁SO₂R₁₂, wherein R₁₁ and R₁₂ are        hydrogen or C₁₋₆alkyl; and    -   R₆, R₇ and R₈ are independently hydrogen or C₁₋₆alkyl; and    -   R₉ is hydrogen or C₁₋₁₀alkyl;    -   or a compound of formula (I) wherein the CO-Y linkage is        replaced by a heterocyclic bioisostere;

WO 01/58895-A1 describes novel compounds having the formula (i):

wherein R₁ is C₁₋₃alkyl optionally substituted with one or morefluorines;

-   -   R₂ is CH₂OCH₃ or 2 or 3-tetrahydrofuranyl;    -   R₃ is a pyrazole, imidazole or isoxazole group of a partial        formula (A), (B) or (C)    -   R₄ is C₁₋₃alkyl; and    -   R₅ and R₆, which may be same or different each represents        C₁₋₃alkyl, halogen, CF₃ or CN;

U.S. Pat. No. 4,769, 387 describes compounds of the formula:

wherein R is (1) hydrogen, (2) C₁ to C₄ alkyl, (3) C₂ to C₄ alkenyl, or(4) NR₂R₃, wherein

-   -   R₂ and R₃ are independently selected from hydrogen, C₁ to C₄        alkyl or hydroxyl, but R₂ and R₃ are not simultaneously        hydroxyl;    -   X (1) oxygen, (2) sulfur, (3) SO₂, or (4) NR₄ wherein R₄ is (1)        hydrogen, (2) C₁ to C₆ alkyl, (3) C₁ to C₆ alkoyl, or (4) aroyl;    -   A is selected from C₁ to C₆ alkylene and C₂ to C₆ alkenylene;    -   Y is selected independently at each occurrence from (1)        hydrogen, (2) halogen, (3) hydroxy, (4) cyano (5)        halosubstituted alkyl, (6) C₁ to C₁₂ alkyl, (7) C₂ to C₁₂        alkenyl, (8) C₁ to C₁₂ alkoxy, (9) C₃ to C₈ cycloalkyl, (10)        aryl, (11) aryloxy, (12) aroyl, (13) C₁ to C₁₂ arylalkyl, (14)        C₂ to C₁₂ arylalkenyl, (15) C₁ to C₁₂ arylalkoxy, (16) C₁ to C₁₂        arylthioalkoxy, and substituted derivatives of (17) aryl, (18)        aryl-oxy, (19) aroyl, (20) C₁ to C₁₂ arylalkyl, (21) C₂ to C₁₂        arylalkenyl, (22) C₁ to C₁₂ arylalkoxy, or (23) C₁ to C₁₂        arylthioalkoxy, wherein substituents are selected from halo,        nitro, cyano C₁ to C₁₂ alkyl, alkoxy, and halosubstituted alkyl;        the number n is 0-4; the group(s) Y may be substituted from any        of the positions on the aryl rings;    -   and M is hydrogen, a pharmaceutically acceptable cation, aroyl,        or C₁ to C₁₂ alkoyl.

U.S. Pat. No. 3,897,453 describes dibenzofuran and dibenzothiophenederivatives of general formula IZ-CHR₁R₂   (I)In which Z is

wherein R₁ is COOH, CHO, or CH₂OH including functional derivativesthereof; R₂ is H or alkyl of 1-4 carbon atoms; R₃ is H, alkyl, alkoxy,alkanoyl, monoalkylamino, dialkylamino, or acylamino, each of up to 4carbon atoms, F, Cl, Br, I, OH, NH₂, NO₂, CN, or CF3; and Y is O or S;with the proviso that at least one of R₂ and R₃ is other than H; and thephysiologically acceptable salts thereof.

WO 98/09934 describes compounds of formula I

Wherein M is a natural (L) alpha amino acid derivative having thestructure

-   -   X is O, S, S(O)_(n), CH₂, CO, or NR_(Q);    -   R_(Q) is hydrogen, C₁-C₆ alkyl or —C₁-C₆ alkyl-phenyl; R is        aside chain of a natural alpha amino acid;    -   R₁ is C₁-C₅ alkoxy, hydroxy, or —NHOR₅;    -   R₂ and R₄ are independently hydrogen, —C₁-C₅ alkyl, phenyl-NO₂,        halogen, —OR₅, —CN, —CO₂R₅, —SO₃R₅, —CHO, —COR₅, —CONR₅R₆,        —(CH₂)_(n)NR₅R₆, —CF₃, or —NHCOR₅;    -   Each R₅ and R₆ are independently hydrogen, C₁-C₅ alkyl; and n is        0 to 2, and the pharmaceutically acceptable salts, esters,        amides and prodrugs thereof.

SUMMARY OF THE INVENTION

Accordingly, the present invention provides novel heterocyclic compoundsof general formula (1)

The invention thus relates to compounds of formula 1,

wherein:

-   -   R¹, R² and R³ may be same or different and are independently        selected from the groups consisting of hydrogen, substituted or        unsubstituted alkyl, substituted or unsubstituted alkenyl,        substituted or unsubstitued alkynyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        cycloalkylakyl, substituted or unsubstituted cycloalkenyl,        substituted or unsubstituted aryl, substituted or unsubstituted        arylalkyl, substituted or unsubstituted heteroaryl, substituted        or unsubstituted heterocyclic group, substituted or        unsubstituted heterocyclylalkyl, substituted or unsubstituted        heteroarylalkyl, —C(O)—R¹, —C(O)O—R¹, C(O)NR¹R¹, —S(O)_(m)—R¹,        —S(O)_(m)—NR¹R¹, nitro, —OH, cyano, amino, formyl, acetyl,        halogen, —OR¹, —SR¹, protecting groups or when two R²        substitutents ortho to each other, may be joined to a form a        saturated or unsaturated cyclic ring, which may optionally        include up to two heteroatoms selected from O, NR¹ or S;    -   wherein P represents oxygen or sulfur preferably O;    -   wherein n represents 0-4;

Ar is substituted or unsubstituted aryl, substituted or unsubstitutedarylalkyl, substituted or unsubstituted heterocyclic ring or substitutedor unsubstituted heteroaryl ring,

Preferably Ar is optionally substituted phenyl, optionally substitutedbenzyl, optionally substituted pyramidine, optionally substitutedpyridyl selected from 4-pyridyl, 3-pyridyl and 2-pyridyl or optionallysubstituted pyridyl-N-oxide selected from 4-pyridyl-N-oxide,3-pyridyl-N-oxide and 2-pyridyl-N-oxide in which optional substituents(one or more) may be same or different and are independently selectedfrom the groups consisting of hydrogen, hydroxyl, halogen, cyano, nitro,carboxyl, trifluoroalkyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkoxy, substituted or unsubstitutedalkoxycarbonyl, substituted or unsubstituted alkylcarbonyl, substitutedor unsubstituted alkylcarbonyloxy, substituted or unsubstituted amino ormono or di substituted or unsubstituted alkylamino. Further preferred Arselected from the group consisting of substituted or unsubstituted4-pyridyl; substituted or unsubstituted 4-pyridyl-N-oxide; substitutedor unsubstituted 3 pyridyl, substituted or unsubstituted 3pyridyl-N-oxide; substituted or unsubstituted 2 pyridyl; and substitutedor unsubstituted 2 pyridyl N-oxide. Further preferred is when the Ar isselected from the group consisting of

Further preferred Ar is

-   -   X is oxygen, S(O)_(m) or NR⁵;    -   R⁵ represents hydrogen, substituted or unsubstituted alkyl,        substituted or unsubstituted alkenyl, substituted or        unsubstitued alkynyl, substituted or unsubstituted cycloalkyl,        substituted or unsubstituted cycloalkylakyl, substituted or        unsubstituted cycloalkenyl, substituted or unsubstituted aryl,        substituted or unsubstituted arylalkyl, substituted or        unsubstituted heteroaryl, substituted or unsubstituted        heterocyclic group, substituted or unsubstituted        heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl,        —C(O)—R¹, —C(O)O—R¹, —C(O)NR¹R¹, —S(O)_(m)—R¹, —S(O)_(m)—NR¹R¹,        nitro, —OH, cyano, amino, formyl, acetyl, halogen, —OR¹, —SR¹        and protecting groups    -   Wherein m is 0, 1 or 2;    -   Y is —C(O)NR⁴, —NR⁴SO₂, —SO₂NR⁴ or —NR⁴C(O) preferably Y is        —C(O)NH—;    -   R⁴ is hydrogen, substituted or unsubstituted alkyl, hydroxyl,        —OR¹, —COOR¹,substituted or unsubstituted aryl, substituted or        unsubstituted heterocyclic ring;    -   and their analogs, their tautomers, their regioisomers, their        stereoisomers, their enantiomers, their diastereomers, their        polymorphs, their pharmaceutically acceptable salts, their        N-oxides, their pharmaceutically acceptable solvates and their        pharmaceutical compositions containing them or a pharmaceutical        acceptable salts thereof.

The substituents in the ‘substituted alkyl’, ‘substituted alkoxy’‘substituted alkenyl’ ‘substituted alkynyl’ ‘substituted cycloalkyl’‘substituted cycloalkylalkyl’ ‘substituted cyclocalkenyl’ ‘substitutedarylalkyl’ ‘substituted aryl’ ‘substituted heterocyclic ring’,‘substituted heteroaryl ring,’ ‘substituted heteroarylalkyl’,‘substituted heterocyclylalkyl ring’, ‘substituted amino’, ‘substitutedalkoxycarbonyl’, ‘substituted cyclic ring’ ‘substituted alkylcarbonyl’,‘substituted alkylcarbonyloxy’ and may be the same or different whichone or more selected from the groups such as hydrogen, hydroxy, halogen,carboxyl, cyano, nitro, oxo (═O), thio(=S), substituted or unsubstitutedalkyl, substituted or unsubstituted alkoxy, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted aryl, substituted or unsubstituted arylalkyl, substitutedor unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl,substituted or unsubstituted amino, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, 'substituted heterocyclylalkylring’ substituted or unsubstituted heteroarylalkyl, substituted orunsubstituted heterocyclic ring, substituted or unsubstiuted guanidine,—COOR^(x), —C(O)R^(x), C(S)R^(x), —C(O)NR^(x)R^(y), —C(O)ONR^(x)R^(y),—NR^(x)CONR^(y)R^(z), —N(R^(x))SOR^(y), —N(R^(x))SO₂R^(y),—(═N—N(R^(x))R^(y)), —NR^(x)C(O)OR^(y), —NR^(x)R^(y), —NR^(x)C(O)R^(y)—,—NR^(x)C(S)R^(y) —NR^(x)C(S)NR^(y)R^(z), —SONR^(x)R^(y)—,—SO₂NR^(x)R^(y)—, —OR^(x), —OR^(x)C(O)NR^(y)R^(z), —OR^(x)C(O)OR^(y),—OC(O)R^(x), —OC(O)NR^(x)R^(y), —R^(x)NR^(y)C(O)R^(z), —R^(x)OR^(y),—R^(x)C(O)OR^(y), —R^(x)C(O)NR^(y)R^(z), —R^(x)C(O)R^(x),—R^(x)OC(O)R^(y), —SR^(x), —SOR^(x), —SO₂R^(x), —ONO₂, wherein R^(x),R^(y) and R^(z) in each of the above groups can be hydrogen atom,substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted aryl, substituted or unsubstitutedarylalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted cycloalkenyl, substituted or unsubstituted amino,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, ‘substituted heterocyclylalkyl ring’ substituted orunsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclicring,

Further preferred is R¹ is substituted alkyl. Most preferred is R¹ isCHF₂. Still further preferred R¹ is unsubstituted alkyl most preferablymethyl. Preferably R² is alkyl, halogen, cyano, nitro, amino,substituted heterocyclic and SO₂NR¹R¹ and n=1, most preferably R² ischloro. Still further prefered R² is substituted alkyl most preferablyCF₃. Still further preferred R¹ is —NH₂. Still further preferred R² isSO₂NR¹R². Most preferably R² is SO₂N(CH₃)₂.

BRIEF DESCRIPTION OF THE DRAWINGS

Graph 1 shows the effect of Example 1 on the inhibition on LPS inducedTNFα release in male Balb/C mice.

Graph 2 shows the effect of Example 1 on arachidonic acid induced earedema in mice.

DETAILED DESCRIPTION OF THE INVENTION

The term ‘alkyl’ refers to a straight or branched hydrocarbon chainradical consisting solely of carbon and hydrogen atoms, containingsolely of carbon and hydrogen atoms, containing no unsaturation, havingfrom one to eight carbon atoms, and which is attached to the rest of themolecule by a single bond, e.g., methyl, ethyl, n-propyl 1-methylethyl(isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), and thelike.

The term “Alkenyl ” refers to aliphatic hydrocarbon group containing acarbon-carbon double bond and which may be a straight or branched orbranched chain having about 2 to about 10 carbon atoms, e.g., ethenyl,1-propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-I-propenyl,1-butenyl, 2-butenyl and the like.

The term “Alkynyl” refers to straight or branched chain hydrocarbylradicals having at least one carbon-carbon triple bond, and having inthe range of about 2 up to 12 carbon atoms (with radicals having in therange of about 2 up to 10 carbon atoms presently being preferred) e.g.,ethynyl, propynyl, butnyl and the like.

The term “Alkoxy” denotes alkyl group as defined above attached viaoxygen linkage to the rest of the molecule. Representative examples ofthose groups are —OCH₃, —OC₂H₅ and the like.

The term “Alkylcarbonyl” denotes alkyl group as defined above attachedvia carbonyl linkage to the rest of the molecule. Representativeexamples of those groups are —C(O)CH₃, —C(O)C₂H₅ and the like.

The term “Alkoxycarbonyl” denotes alkoxy group as defined above attachedvia carbonyl linkage to the rest of the molecule. Representativeexamples of those groups are —C(O)—OCH₃, —C(O)—OC₂H₅ and the like.

The term “Alkylcarbonyloxy” denotes alkylcarbonyl group as defined aboveattached via oxygen linkage to the rest of the molecule. Representativeexamples of those groups are O—C(O)CH₃, —O—C(O)C₂H₅ and the like.

The term “Alkylamino” denotes alkyl group as defined above attached viaamino linkage to the rest of the molecule. Representative examples ofthose groups are —NH₂CH₃, —NH(CH₃)₂, —N(CH₃)₃ and the like.

The term “cycloalkyl” denotes a non-aromatic mono or multicyclic ringsystem of about 3 to 12 carbon atoms such as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and examples of multicyclic cycloalkyl groupsinclude perhydronapththyl, adamantyl and norbornyl groups bridged cyclicgroup or sprirobicyclic groups e.g sprio (4,4) non-2-yl.

The term “cycloalkylalkyl” refers to cyclic ring-containing radicalscontaining in the range of about 3 up to 8 carbon atoms directlyattached to alkyl group which are then attached to the main structure atany carbon from alkyl group that results in the creation of a stablestructure such as cyclopropylmethyl, cyclobuyylethyl, cyclopentylethyl,and the like.

The term “cycloalkenyl” refers to cyclic ring-containing radicalscontaining in the range of about 3 up to 8 carbon atoms with at leastone carbon-carbon double bond such as cyclopropenyl, cyclobutenyl,cyclopentenyl and the like.

The term “aryl” refers to aromatic radicals having in the range of 6 upto 14 carbon atoms such as phenyl, naphthyl, tetrahydronapthyl, indanyl,biphenyl and the like.

The term “arylalkyl” refers to an aryl group as defined above directlybonded to an alkyl group as defined above. e.g., —CH₂C₆H₅, —C₂H₅C₆H₅ andthe like.

The term “heterocyclic ring” refers to a stable 3- to 15 membered ringradical which consists of carbon atoms and from one to five heteroatomsselected from the group consisting of nitrogen, phosphorus, oxygen andsulfur. For purposes of this invention, the heterocyclic ring radicalmay be a monocyclic, bicyclic or tricyclic ring system, which mayinclude fused, bridged or spiro ring systems, and the nitrogen,phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ringradical may be optionally oxidized to various oxidation states. Inaddition, the nitrogen atom may be optionally quaternized; and the ringradical may be partially or fully saturated (i.e., heteroaromatic orheteroaryl aromatic). Examples of such heterocyclic ring radicalsinclude, but are not limited to, azetidinyl, acridinyl, benzodioxolyl,benzodioxanyl, benzofurnyl, carbazolyl cinnolinyl dioxolanyl,indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl,phenothiazinyl, phenoxazinyl, phthalazil, pyridyl, pteridinyl, purinyl,quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazoyl,imidazolyl tetrahydroisouinolyl, piperidinyl, piperazinyl,2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl,azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazinyl, pyrimidinylpyridazinyl, oxazolyl oxazolinyl oxasolidinyl, triazolyl, indanyl,isoxazolyl, isoxasolidinyl, morpholinyl, thiazolyl, thiazolinyl,thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl,isoindolyl, indolinyl, isoindolinyl, octahydroindolyl,octahydroisoindolyl quinolyl, isoquinolyl, decahydroisoquinolyl,benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl,benzooxazolyl, furyl, tetrahydrofurtyl, tetrahydropyranyl, thienyl,benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide thiamorpholinylsulfone, dioxaphospholanyl, oxadiazolyl, chromanyl, isochromanyl and thelike.

The term “heteroaryl” refers to heterocyclic ring radical as definedabove. The heteroaryl ring radical may be attached to the main structureat any heteroatom or carbon atom that results in the creation of astable structure.

The heterocyclic ring radical may be attached to the main structure atany heteroatom or carbon atom that results in the creation of a stablestructure.

The term “heteroarylalkyl” refers to heteroaryl ring radical as definedabove directly bonded to alkyl group. The heteroarylalkyl radical may beattached to the main structure at any carbon atom from alkyl group thatresults in the creation of a stable structure.

The term “heterocyclyl” refers to a heterocylic ring radical as definedabove. The heterocylyl ring radical may be attached to the mainstructure at any heteroatom or carbon atom that results in the creationof a stable structure.

The term “heterocyclylalkyl” refers to a heterocylic ring radical asdefined above directly bonded to alkyl group. The heterocyclylalkylradical may be attached to the main structure at carbon atom in thealkyl group that results in the creation of a stable structure.

The term “cyclic ring ” refers to a cyclic ring containing 3-10 carbonatoms.

The term “protecting group” refers to carbobenzyloxy (CBZ) orTert.butyloxy, carbonyl (BOC) and the like.

The term “halogen” refers to radicals of fluorine, chlorine, bromine andiodine.

Pharmaceutically acceptable salts forming part of this invention includesalts derived from inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu,Zn, Mn; salts of organic bases such as N,N′-diacetylethylenediamine,glucamine, triethylamine, choline, hydroxide, dicyclohexylamine,metformin, benzylamine, trialkylamine, thiamine, and the like; chiralbases like alkylphenylamine, glycinol, phenyl glycinol and the like,salts of natural amino acids such as glycine, alanine, valine, leucine,isoleucine, norleucine, tyrosine, cystine, cysteine, methionine,proline, hydroxy proline, histidine, omithine, lysine, arginine, serine,and the like; quaternary ammonium salts of the compounds of inventionwith alkyl halides, alkyl sulphats like MeI, (Me)₂SO₄ and the like,non-natural amino acids such as D-isomers or substituted amino acids;guanidine, substituted guanidine wherein the substituents are selectedfrom nitro, amino, alkyl, alkenyl, alkynyl, ammonium or substitutedammonium salts and aluminum salts. Salts may include acid addition saltswhere appropriate which are, sulphates, nitrates, phosphates,perchlorates, borates, hydrohalides, acetates, tartrates, maleates,citrates, succinates, palmoates, methanesulphonates, benzoates,salicylates, benzenesulfonates, ascorbates, glycerophosphates,ketoglutarates and the like. Pharmaceutically acceptable solvates may behydrates or comprise other solvents of crystallization such as alcohols.

Another object of the invention is a method of treating inflammatorydiseases, disorders and conditions characterized by or associated withan undesirable inflammatory immune response and all disease andconditions induced by or associated with an excessive secretion of TNF-αand PDE-4 which comprises administering to a subject a therapeuticallyeffective amount of a compound according to Formula I.

Another object of the invention is a method of treating inflammatoryconditions and immune disorders in a subject in need thereof whichcomprises administering to said subject a therapeutically effectiveamount of a compound according to Formula I.

Preferred inflammatory conditions and immune disorders are chosen fromthe group consisting of asthma, bronchial asthma, chronic obstructivepulmonary disease, allergic rhinitis, eosinophilic granuloma, nephritis,rheumatoid arthritis, cystic fibrosis, chronic bronchitis, multiplesclerosis, Crohns disease, psoraisis, uticaria, adult vernalcojunctivitis, respiratory distress syndrome, rhematoid spondylitis,osteoarthritis, gouty arthritis, uteltis, allergic conjunctivitis,inflammatory bowel conditions, ulcerative coalitis, eczema, atopicdermatitis and chronic inflammation. Further preferred are allergicinflammatory conditions.

Further preferred are inflammatory conditions and immune disordersselected from the group consisting of inflammatory conditions or immunedisorders of the lungs, joints, eyes, bowels, skin and heart.

Further preferred are inflammatory conditions chosen from the groupconsisting of bronchial asthma, nepritis, and allergic rhinitis.

Another object of the invention is a method for abating inflammation inan affected organ or tissue including delivering to the organ or tissuea therapeutically effective amount of a compound represented by acompound according to Formula 1.

Another object of the invention is a method of treating diseases of thecentral nervous system in a subject in need thereof which comprisesadministering to said subject a therapeutically effective amount of acompound according to Formula 1.

Preferred diseases of the central nervous system are chosen from thegroup consisting of depression, amnesia, dementia, Alzheimers disease,cardiac failure, shock and cerebrovascular disease.

Another object of the invention is a method of treating insulinresistant diabetes in a subject in need thereof which comprisesadministering to said subject a therapeutically effective amount of acompound according to Formula 1.

“Treating” or “treatment” of a state, disorder or condition includes:

(1) preventing or delaying the appearance of clinical symptoms of thestate, disorder or condition developing in a mammal that may beafflicted with or predisposed to the state, disorder or condition butdoes not yet experience or display clinical or subclinical symptoms ofthe state, disorder or condition,

(2) inhibiting the state, disorder or condition, i.e., arresting orreducing the development of the disease or at least one clinical orsubclinical symptom thereof, or

(3) relieving the disease, i.e., causing regression of the state,disorder or condition or at least one of its clinical or subclinicalsymptoms.

The benefit to a subject to be treated is either statisticallysignificant or at least perceptible to the patient or to the physician

A “therapeutically effective amount” means the amount of a compoundthat, when administered to a mammal for treating a state, disorder orcondition, is sufficient to effect such treatment The “therapeuticallyeffective amount” will vary depending on the compound, the disease andits severity and the age, weight, physical condition and responsivenessof the mammal to be treated.

The four classic symptoms of acute inflammation are redness, elevatedtemperature, swelling, and pain in the affected area, and loss offunction of the affected organ.

Symptoms and signs of inflammation associated with specific conditionsinclude:

-   -   rheumatoid arthritis—pain, swelling, warmth and tenderness of        the involved joints; generalized and morning stiffness;    -   insulin-dependent diabetes mellitus- insulitis; this condition        can lead to a variety of complications with an inflammatory        component, including: retinopathy, neuropathy, nephropathy,        coronary artery disease, peripheral vascular disease, and        cerebrovascular disease;    -   autoimmune thyroiditis—weakness, constipation, shortness of        breath, puffiness of the face, hands and feet, peripheral edema,        bradycardia;    -   multiple sclerosis—spasticity, blurry vision, vertigo, limb        weakness, paresthesias;    -   uveoretinitis—decreased night vision, loss of peripheral vision;    -   lupus erythematosus—joint pain, rash, photosensitivity, fever,        muscle pain, puffiness of the hands and feet, abnormal        urinalysis (hematuria, cylinduria, proteinuria),        glomerulonephritis, cognitive dysfunction, vessel thrombosis,        pericarditis;    -   scleroderma—Raynaud's disease; swelling of the hands, arms, legs        and face; skin thickening; pain, swelling and stiffness of the        fingers and knees, gastrointestinal dysfunction, restrictive        lung disease; pericarditis,; renal failure;    -   other arthritic conditions having an inflammatory component such        as rheumatoid spondylitis, osteoarthritis, septic arthritis and        polyarthritis—fever, pain, swelling, tenderness;    -   other inflammatory brain disorders, such as meningitis,        Alzheimer's disease, AIDS dementia encephalitis—photophobia,        cognitive dysfunction, memory loss;    -   other inflammatory eye inflammations, such as        retinitis—decreased visual acuity;    -   inflammatory skin disorders, such as, eczema, other dermatites        (e.g., atopic, contact), psoriasis, burns induced by UV        radiation (sun rays and similar UV sources)—erythema, pain,        scaling, swelling, tenderness;    -   inflammatory bowel disease, such as Crohn's disease, ulcerative        colitis—pain, diarrhea, constipation, rectal bleeding, fever,        arthritis;    -   asthma—shortness of breath, wheezing,    -   other allergy disorders, such as allergic rhinitis—sneezing,        itching, runny nose    -   conditions associated with acute trauma such as cerebral injury        following stroke—sensory loss, motor loss, cognitive loss;    -   heart tissue injury due to myocardial ischemia—pain, shortness        of breath;    -   lung injury such as that which occurs in adult respiratory        distress syndrome—shortness of breath, hyperventilation,        decreased oxygenation, pulmonary infiltrates;    -   inflammation accompanying infection, such as sepsis, septic        shock, toxic shock syndrome—fever, respiratory failure,        tachycardia, hypotension, leukocytosis;    -   other inflammatory conditions associated with particular organs        or tissues, such as nephritis (e.g.,        glomerulonephritis)—oliguria, abnormal urinalysis;    -   inflamed appendix—fever, pain, tenderness, leukocytosis;    -   gout—pain, tenderness, swelling and erythema of the involved        joint, elevated serum and/or urinary uric acid;    -   inflamed gall bladder—abdominal pain and tenderness, fever,        nausea, leukocytosis;    -   chronic obstructive pulmonary disease—shortness of breath,        wheezing;    -   congestive heart failure—shortness of breath, rates, peripheral        edema;    -   Type II diabetes—end organ complications including        cardiovascular, ocular, renal, and peripheral vascular disease    -   lung fibrosis—hyperventilation, shortness of breath, decreased        oxygenation;    -   vascular disease, such as atherosclerosis and restenosis—pain,        loss of sensation, diminished pulses, loss of function    -   and alloimmunity leading to transplant rejection—pain,        tenderness, fever.

Subclinical symptoms include without limitation diagnostic markers forinflammation the appearance of which may precede the manifestation ofclinical symptoms. One class of subclinical symptoms is immunologicalsymptoms, such as the invasion or accumulation in an organ or tissue ofproinflammatory lymphoid cells or the presence locally or peripherallyof activated proinflammatory lymphoid cells recognizing a pathogen or anantigen specific to the organ or tissue. Activation of lymphoid cellscan be measured by techniques known in the art.

“Delivering” a therapeutically effective amount of an active ingredientto a particular location within a host means causing a therapeuticallyeffective blood concentration of the active ingredient at the particularlocation. This can be accomplished e.g., by local or by systemicadministration of the active ingredient to the host

“A subject” or “a patient” or “a host” refers to mammalian animals,preferably human.

Some of the representative compounds according to the present inventionare specified below but should not construed to be limited thereto;

-   -   1) N-(3,5-dichloropyrid-4-yl)-4methoxy        dibenzo[b,d]furan-1-carboxamide    -   2) N-(3,5-dichloropyrid-4-yl)-4-methoxy        dibenzo[b,d]furan-1-carboxamide-N1-oxide    -   3) N-(pyrid-4-yl)-4-methoxy dibenzo[b,d]furan-1-carboxamide    -   4) N-(pyrid-4-yl)-4methoxy        dibenzo[b,d]furan-1-carboxamide-N1-oxide    -   5) N-(2-chloropyrid-3-yl)-4-methoxy        dibenzo[b,d]furan-1-carboxamide    -   6) N-(4-fluorophenyl)-4-methoxy dibenzo[b,d]furan-1-carboxamide    -   7) N-(pyrid-3-yl)-4-methoxy dibenzo[b,d]furan-1-carboxamide    -   8) N-(pyrid-3-yl)-4-methoxy        dibenzo[b,d]furan-1-carboxamide-N1-oxide    -   9) N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-trifluoromethyl        dibenzo[b,d]furan-1-carboxamide    -   10) N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-trifluoromethyl        dibenzo[b,d]furan-1-carboxamide-N1-oxide    -   11) N-(pyrid-4yl)-4-methoxy-8-trifluoromethyl        dibenzo[b,d]furan-1-carboxamide    -   12)        N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-trifluoromethyl        dibenzo[b,d]furan-1-carboxamide    -   13) N-(3,5-chloropyrid-4-yl)-4-difluoromethoxy-8-trifluoromethyl        dibenzo[b,d]furan-1-carboxamide-N1-oxide    -   14) N-(pyrid-4-yl)-4fluoromethoxy-8-trifluoromethyl        dibenzo[b,d]furan-1-carboxamide    -   15) N-(pyrid-4-yl)-4-difluoromethoxy-8-trifluoromethyl        dibenzo[b,d]furan-1-carboxamide-N1-oxide    -   16) N-(pyrid-3-yl)-4-difluoromethoxy-8-trifluoromethyl        dibenzo[b,d]furan-1-carboxamide    -   17) N-(pyrid-3-yl)-4-difluoromethoxy-8-trifluoromethyl        dibenzo[b,d]furan-1-carboxamide-N1-oxide    -   18) N-(pyrid-2-yl)-4-difluoromethoxy-8-trifluoromethyl        dibenzo[b,d]furan-1-carboxamide    -   19) N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy        dibenzo[b,d]furan-1-carboxamide    -   20) N-(pyrid-4yl)-4-difluoromethoxy        dibenzo[b,d]furan-1-carboxamide    -   21) N-(pyrid-4-yl)-4-difluoromethoxy        dibenzo[b,d]furan-1-carboxamide-N1-oxide    -   22) N-(pyrid-3-yl)-4-difluoromethoxy        dibenzo[b,d]furan-1-carboxamide    -   23) N-(pyrid-3-yl)-4-difluoromethoxy        dibenzo[b,d]furan-1-carboxamide-N1-oxide    -   24) N-(5-chloropyrid-2-yl)-4-difluoromethoxy        dibenzo[b,d]furan-1-carboxamide    -   25) N-(3,5-dichloropyrid-4-yl)-4-cyclopropylmethoxy        dibenzo[b,d]furan-1-carboxamide    -   26) N-(3,5-dichloropyrid-4-yl)-4-cyclopropylmethoxy        dibenzo,d]furan-1-carboxamide-N1-oxide    -   27) N-(pyrid-4-yl)-4-cyclopropylmethoxy        dibenzo[b,d]furan-1-carboxamide    -   28) N-(pyrid-4-yl)-4-cyclopropylmethoxy        dibenzo[b,d]furan-1-carboxamide-N1-oxide    -   29) N-(pyrid-3-yl)-4-cyclopropylmethoxy        dibenzo[b,d]furan-1-carboxamide    -   30) N-(pyrid-3-yl)-4-cyclopropylmethoxy        dibenzo[b,d]furan-1-carboxamide-N1-oxide    -   31) N-(3,5-dichloropyrid-4-yl)-4-isopropyloxy        dibenzo[b,d]furan-1-carboxamide    -   32) N-(3,5-dichloropyrid-4-yl)-4-isopropyloxy        dibenzo[b,d]furan-1-carboxamide-N1-oxide    -   33) N-(pyrid-4-yl)-4-isopropyloxy        dibenzo[b,d]furan-1-carboxamide    -   34) N-(pyrid-4-yl)-4-isopropyloxy        dibenzo[b,d]furan-1-carboxamide-N1-oxide    -   35) N-(pyrid-3-yl)-4-isopropyloxy        dibenzo[b,d]furan-1-carboxamide    -   36) N-(pyrid-3-yl)-4-isopropyloxy        dibenzo[b,d]furan-1-carboxamide-N1-oxide    -   37) N-(3,5-dichloropyrid-4-yl)-4-benzyloxy        dibenzo[b,d]furan-1-carboxamide    -   38) N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-nitro        dibenzo[b,d]furan-1-carboxamide    -   39) N-(pyrid-4-yl)-4-methoxy-8-nitro        dibenzo[b,d]furan-1-carboxamide    -   40) N-pyrid-3-yl)-4-methoxy-8-nitro        dibenzo[b,d]furan-1-carboxamide    -   41)        N-(3,5dichloropyrid-4-yl)-4-methoxy-8-chloro-dibenzo[b,d]furan-1-carboxamide    -   42)        N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-bromo-dibenzo[b,d]furan-1-carboxamide    -   43)        N-(pyrid-4-yl)-4-methoxy-8-bromo-dibenzo[b,d]furan-1-carboxamide    -   44)        N-(pyrid-3-yl)-4-methoxy-8-bromo-dibenzo[b,d]furan-1-carboxamide    -   45)        N-(3,5-dichloropyrid-4yl)-4methoxy-8-iodo-dibenzo[b,d]furan-1-carboxamide    -   46)        N-(pyrid-4-yl)-4-methoxy-8-iodo-dibenzo[b,d]furan-1-carboxamide    -   47)        N-(pyrid-3-yl)-1methoxy-8-iodo-dibenzo[b,d]furan-1-carboxamide    -   48) N-(4-methylpyrimid-2-yl)-4-methoxy dibenzo        [b,d]furan-1-carboxamide    -   49) N-(2,5- dichlorophenyl)-4-methoxy        dibenzo[b,d]furan-1-carboxamide    -   50) a.N-(3,5-dichloropyrid-4-yl)-4ethoxycarbomethoxy        dibenzo[b,d]furan-1-carboxamide        -   b.N-(3,5-dichloropyrid-4-yl)-4-hydroxycarbomethoxydibenzo[b,d]furan-1-carboxamide    -   51) N-(3,5-dichloropyrid-4-yl)-4-methoxy        dibenzo[b,d]furan-2-carboxamide    -   52) N-(3,5-dichloropyrid-4-yl)-4-methoxy        dibenzo[b,d]furan-3-carboxamide    -   53) N4-(4-methoxy dibenzo[b,d]furan-1-yl) isonicotinamide    -   54) N-(3,5-dichloropyrid-4-yl)-4-methoxy        dibenzo[b,d]furan-1-sulfonamide    -   55)        N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-amino-dibenzo[b,d]furan-1-carboxamide    -   56)        N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-dibenzo[b,d]furan-1-carboxamide-N-oxide    -   57)        N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-cyano-dibenzo[b,d]furan-1-carboxamide    -   58)        N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-nitro-dibenzo[b,d]furan-1-carboxamide    -   59)        N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-amino-dibenzo[b,d]furan-1-carboxamide    -   60)        3,5-Dichloro-4-(4-ethoxydibenzo[b,d]furan-1-ylcarboxamido)pyridine    -   61) N1-Benzyl-4-cyclopentyloxydibenzo[b,d]furan-1-carboxamide    -   62)        4-(4-Cyclopentyloxydibenzo[b,d]furan-1-ylcarboxamido)pyridine    -   63)        3,5-Dichloro-4-cyclopentyloxydibenzo[b,d]furan-1-ylcarboxamido)pyridine.    -   64)        4-(4-Methylsulfanyldibenzo[b,d]furan-1-ylcarboxamido)pyridine    -   65) N3-(4-Methoxydibenzo[b,d]furan-1-yl)nicotinamide    -   66) N1-Benzyl-4-methoxydibenzo[b,d]furan-1-sulfonamide    -   67) 4-(4-Methoxydibenzo[b,d]furan-1-ylsulfonamido)pyridine    -   68)        3,5-Dichloro-4-(4-ethoxydibenzo[b,d]furan-1-ylcarboxamido)pyridine-N-oxide    -   69)        3,5-Dichloro-4-cyclopentyloxydibenzo[b,d]furan-1-ylcarboxamido)pyridine-N-oxide    -   70)        N-Formyl-1-methoxy-4-[4-methoxyphenylaminosulphonyl]-9H-carbazole    -   71) 1-methoxy-4-[4-methoxyphenylaminosulphonyl]-9H-carbazole.    -   72)        N-Formyl-1-methoxy-4-[4-methylphenylaminosulphonyl]-9H-carbazole.    -   73) 1-methoxy-4-[4-methylphenylaminosulphonyl]-9H-carbazole.    -   74)        1-methoxy-4-[4-methylphenylaminosulphonyl-N′-methyl]-9H-carbazole.    -   75) 1-methoxy-4-[4-methylphenylaminosulphonyl-N′-methyl]-9methyl        carbazole.    -   76) 1-methoxy-4-[4-pyridinylaminosulphonyl]-9H-carbazole.    -   77) N4-(2,6-Dichlorophenyl)-1-methoxy-9H-4-carbazolsulphonamide.    -   78)        N4-(2,6-Dichlorophenyl)-9-formyl-1-methoxy-9H-4-carbazolsulphonamide.    -   79) N4-(4-pyridyl)-1-methoxy-9H-4-carbazole carboxamide.    -   80) N4-(3,5-dichloro-4-pridyl)-1-methoxy-9H-4-carbazole        carboxamide.    -   81) N4-(3,5dichloro-4-pyridyl)-6-chloro-1-methoxy-9H-4-carbazole        carboxamide.    -   82)        N4-(3,5-dichloro-4-pyridyl)-9-benzyl-6-chloro-1-methoxy-9H-4-carbazole        carboxamide.    -   83)        N4-(3,5-dichloro-4-pyridyl)-6-chloro-9-cyclohexylmethyl-1-methoxy-9H-4-carbazole        carboxamide.    -   84)        N4-(3,5-dichloro-4-pyridyl)-6-chloro-9-(4-fluorobenzyl)-1-methoxy-9H-4-carbazole        carboxamide.    -   85)        N4-(3,5-dichloro-4-pyridyl)-6-chloro-9-(4-methoxybenzyl)-1-methoxy-9H-4-carbazolecarboxamide.    -   86)        N4-(3,5chloro-4-pyridyl)-9-(4-fluorobenzyl)-1-methoxy-9H-4-carbazole        carboxamide.    -   87) N4-(4-pyridyl)-9-(4-fluorobenzyl)-1-methoxy -9H-4-carbazole        carboxamide.    -   88)        N4-(3,5-dichloro-4-pyridyl)-9-benzyl-1-methoxy-9H-4-carbazolecarboxamide.    -   89)        N4-(3,5-dichloro-4-pyridyl)-9-benzyl-1-ethoxy-9H-4-carbazolecarboxamide.    -   90)        N4-(3,5-dichloro-4-pyridyl)-9-benzyl-6-chloro-1-ethoxy-9H-4-carbazolecarboxamide    -   91) N4-(4-pyridyl)-9-benzyl-1-ethoxy-9H-4-carbazolecarboxamide    -   92)        N4-(3-pyridyl)-6-chloro-9-(4-fluorobenzyl)-1-methoxy-9H-4-carbazolecarboxamide.    -   93)        N4-(4-pyridyl)-6-chloro-9-(4-fluorobenzyl)-1-methoxy-9H-4-carbazolecarboxamide    -   94)        N4-(3,5-dichloro-4-pyridyl)8-chloro-9-cyclohexylmethyl-1-methoxy-9H-4-carbazole        carboxamide.    -   95)        N4-(3,5-dichloro-4-pyridyl)-8-chloro-9-(4-Fluorobenzyl)-1-methoxy-9H-4-carbazole        carboxamide.    -   96)        N4-(3,5-dichloro-4-pyridyl)-6-chloro-1-methoxy-9-methyl-9H-4-carbazole        carboxamide.    -   97) N4-(3,5-dichloro-4-pyridyl        N-oxide)-6-chloro-9-(4-fluorobenzyl)-1-methoxy-9H-4-carbazolecarboxamide.    -   98) N4-(3,5-dichloro-4-pyridyl        N-oxide)-6-chloro-9-(4-methoxybenzyl)-1-methoxy-9H-4-carbazolecarboxamide.    -   99) N4-(3,5-dichloro-4-pyridyl        N-oxide)-6-chloro-9-cyclohexylmethyl-1-methoxy-9H-4-carbazolecarboxamide.    -   100)        N4-(3,5-dichloro-4-pyridyl)-9-methyl-1-methoxy-9H-4-carbazolecarboxamide.    -   101)        3,5-Dichloro-4-(4-methoxydibenzo[b,d]-thiophen-1-ylcarboxamido)pyridine    -   102)        3,5-dichloro-4-(4-cyclopentyloxydibenzo[b,d]-thiophen-1-ylcarboxamido)pyridine    -   103)        N1-(4-methoxyphenyl)-4-methoxydibenzo[b,d]thiophene-1-carboxamide    -   104)        N1-(4-methoxyphenyl)-4-methoxydibenzo[b,d]thiophene-1-carboxamide-5,5-dioxide    -   105)        N1-(4-chlorophenyl)-4-methoxydibenzo[b,d]thiophene-1-carboxamide    -   106) 4-(4-methoxydibenzo[b,d]thiophene-1-ylcarboxamido)pyrdine    -   107)        4-(4-cylopentyloxydibezo[b,d]thiophene-1-ylcarboxamido)pyridine    -   108)        3,5-dichloro-4-(4-cyclopentyloxydibenzo[b,d]-thiophen-5,5-dioxide-1-ylcarboxamido)pyridine-N-oxide    -   109)        3,5-dichloro-4-(4-methoxydibenzo[b,d]-thiophen-5,5-dioxide-1-ylcarboxamido)pyridine-N-oxide    -   110)        3,5Dichloro-4-(4-methoxydibenzo[b,d]-thiophen-5,5-dioxide-1-ylcarboxamido)pyridine.    -   111)        3,5Dichloro-4-(4-difluoromethoxydibenzo[b,d]-thiophen-1-ylcarboxamido)pyridine.    -   112)        N1-(4-methoxyphenyl)-4-methoxydibenzo[b,d]thiophene-1-sulfonamide.    -   113) 2-(4-Methoxydibenzo[b,d]thiophen-1-ylcarboxamido)-pyridine.    -   114) 4-(4-Ethoxydibenzo[b,d]thiophen-1-ylcarboxamido)-pyridine.    -   115) N1 4-methoxyphenyl)-N8,        8-dimethyl-4-methoxydibenzo[b,d]thiophen-8,1-disulfonamide.    -   116) 3-(4-Methoxydibenzo[b,d]thiophen-1-ylcarboxamido)-pyridine.    -   117)        3,5-Dichloro-4-(6-ethyl-4-methoxydibenzo[b,d]-thiophen-1-ylcarboxamido)pyridine    -   118) 3,5,dichloro-4-(4-ethoxy-dibenzo[b,d        ]thiophen-1-yl-carboxamido)pyridine.    -   119)        3-(4-Methoxydibenzo[b,d]thiophene-5,5dioxide-1-ylcarboxamido)-pyridine.    -   120)        3,5-Dichloro-4-(4-benzyloxydibenzo[b,d]-thiophen-1-ylcarboxamido)pyridine    -   121)        N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-(pyrrolidine-2-one-1-yl)-dibenzo[b,d]furan-1-carboxamide

The compounds according to the invention may be prepared by thefollowing processes. The symbols P, Ar, X, Y, R¹, R², R³, R⁴ and R⁵ whenused in the below formulae below are to be understood to present thosegroups described above in relation to formula (1) unless otherwiseindicated

The present invention discloses a process for the preparation ofcompounds of general formula (1).

In one embodiment the compounds of formula 1 where Y is —CONR⁴, can beprepared by reacting the acid halide or the mixed anhydride of thecommon intermediate of formula (10) (wherein FG is COOH) or of formula(11) (which is obtained from formula (10) wherein FG is alkyl, formyl,cyano, halogen, nitro, amino and the like by conventional methods) withan appropriate amine of the formula ArNHR⁴ using standard conditionsknown in the literature.

The common intermediate of the formula (10) and/or of the formula (11)can be synthesized by using any of the general process described insynthetic schemes I to VI.

The desired compounds of formula 1 obtained are then converted intotheir salts and/or the N-oxides and, if desired, salts of the compoundsof formula 1 obtained are then converted into the free compounds.

In the above scheme I wherein P, X R¹, R²and R³ have the meaningsdescribed above intermediate (14) can be synthesized by reacting theappropriate substituted nitrobenzene of

the formula (12) (wherein Z is a halogen,) with an appropriatelysubstituted or unsubstituted aromatic group of the formula (13) (whereinFG is alkyl, formyl, cyano, halogen, nitro, amino, carboxylic acid groupand the like) under appropriate basic conditions. Intermediate (14) canbe reduced under standard reducing conditions (raney nickel/hydrazine,iron/ammonium chloride, hydrogenation using Pd/C, and the like) to theamino compound of the formula (15). The intermediate (15) can becyclized to the tricyclic intermediate of the formula (10) bydiazotization followed by standard coupling methods (cuprous oxide in0.1N sulfuric acid, copper in DMSO). If the functional group FG in (13)is other than the carboxylic acid, then it can be converted to thecarboxylic acid at any stage of the synthetic process as permitted bythe chemistry of the synthetic process. If in the intermediate offormula (10) FG is alkyl formyl, cyano, halogen, nitro, amino, then theintermediate (10) can be transformed to the intermediate of formula (11)by conventional methods described in the literature (for example if FGis methyl then the methyl group can be oxidized using manganese orchromium reagents of to the carboxylic acid group; if FG is cyano groupthen the cyano group could be hydrolysed to the carboxylic acid; if FGis bromine then it could be transformed to carboxylic acid vialithiation followed by treatment with carbon dioxide).

Alternatively, the common intermediate of formula (10) and/or of formula(11) can be synthesized by the process described in scheme II

In the above scheme II wherein P, X R¹, R²and R³ have the meaningsdescribed above and wherein A is a halogen, or —OMs or —OTs(Ms=methanesulfonyl group; Ts=p-toluenesulfonyl group) or —B(OH)₂, B₁ isa halogen, G is an appropriate protecting group (benzyloxy carbonyl,t-butyloxycarbonyl, isopropyl, cyclopentyl, ally, acetyl, benzyl and thelikes), FG is alkyl, formyl, cyano, halogen, nitro, amino, carboxylicacid group and the like and Z is a halogen, preferably bromine oriodine, intermediate (18) can synthesized by coupling the substitutedaryl group of the formula I with an appropriately substituted aryl groupof formula (17) using standard methods known in the literature.(palladium acetate in DMF or glacial acetic acid, nickel catalyst inpyridine or DMF, tetrakistriphenylphosphinepalladium in DMF and thelike). Intermediate (18) can be deprotected to obtain intermediate (19)which then further cyclized under basic conditions (potassium salts inDMP or DMSO, NaH in DMF or DMSO and the like) to the tricyclicintermediate of formula (10). If the functional group FG in (17) isother than the carboxylic acid, then it can be converted to thecarboxylic acid at any stage of the synthetic process as permitted bythe chemistry of the synthetic process. If in the intermediate offormula (10) FG is alkyl, formyl, cyano, halogen, nitro, amino, thenintermediate (10) can be transformed to the intermediate of formula (11)by conventional methods described in the literature (for example if FGis methyl then the methyl group can be oxidized using manganese orchromium reagents of to the carboxylic acid group; if FG is cyano groupthen the cyano group could be hydrolysed to the carboxylic acid; if FGis bromine then it could be transformed to carboxylic acid vialithiation followed by treatment with carbon dioxide).

Alternatively, the common intermediate of formula (10) and I or offormula (11) can be synthesized by the process described in scheme III.

In the above scheme III wherein P, X, R¹, R²and R³ have the meaningsdescribed above and wherein Z is a halogen, FG is alkyl, formyl, cyano,halogen, nitro, amino, carboxylic acid group and the like, intermediate(21) can synthesized by reacting the halocyclohexanone of the formula(20) with appropriately substituted aryl group of the formula (13)underbasic conditions (potassium salts in DMF or DMSO, NaH in DMF or DMSO andthe like). Intermediate (21) can be cyclized under acidic conditions(polyphosphoric acid or methanesulfonic acid) and oxidized (Pd/C indiphenyl ether or dichlorobenzene, DDQ and the like) to the dibenzofuranintermediate of formula (3). The substituents R² can be introduced bystandard electrophilic substitution reactions described in theliterature on intermediate (22) to provide the intermediate of theformula (10). If the functional group FG in (13) is other than thecarboxylic acid, then it can be converted to the carboxylic acid at anystage of the synthetic process as permitted by the chemistry of thesynthetic process. If in the intermediate of formula (10) FG is alkyl,formyl, cyano, halogen, nitro, amino, then the intermediate (10) can betransformed to the intermediate of formula (11) by conventional methodsdescribed in the literature. (for example if FG is methyl then themethyl group can be oxidized using manganese or chromium reagents of tothe carboxylic acid group; if FG is cyano group then the cyano groupcould be hydrolysed to the carboxylic acid; if FG is bromine then itcould be transformed to carboxylic acid via lithiation followed bytreatment with carbon dioxide).

Alternatively, the common intermediate of formula (10) and/or of formula(11) can be synthesized by the process described in scheme IV.

In the above scheme IV wherein P, X, R¹, R²and R³ have the meaningsdescribed above and wherein Z is a halogen, FG is alkyl, formyl, cyano,halogen, nitro, amino, carboxylic acid group and the like, Hal is Br orI, intermediate (24) can synthesized by reacting the substituted arylgroup of the formula A with appropriately substituted aryl group of theformula (13.a) under standard basic conditions (potassium salts in DMFor DMSO, NaH in DMF or DMSO and the like). Intermediate (24) can becyclized under standard palladium catalyzed coupling conditions(palladium acetate in DMF or glacial acetic acid, nickel catalyst inpyridine or DMF, tetrakistriphenylphosphinepalladium in DMF and thelike) to the dibenzofuran intermediate of the formula (10). If thefunctional group FG in (13.a) is other than the carboxylic acid, then itcan be converted to the carboxylic acid at any stage of the syntheticprocess as permitted by the chemistry of the synthetic process. If inthe intermediate of formula (10) FG is alkyl, formyl, cyano, halogen,nitro, amino, then intermediate (10) can be transformed to theintermediate of formula (11) by conventional methods described in theliterature. (for example if FG is methyl then the methyl group can beoxidized using manganese or chromium reagents of to the carboxylic acidgroup; if FG is cyano group then the cyano group could be hydrolysed tothe carboxylic acid; if FG is bromine then it could be transformed tocarboxylic acid via lithiation followed by treatment with carbondioxide).

Alternatively, the common intermediate of formula (10) and/or offormula( 11) can be synthesized by the process described in scheme V.

In the above scheme V, wherein P, X, R¹, R²and R³ have the meaningsdescribed above and wherein FG is alkyl, formyl, cyano, halogen, nitro,amino, carboxylic acid group and the like, the substituents R² and/or R³can also be introduced by standard electrophilic substitution reactionson the tricyclic intermediate of formula (25) which may be synthesizedusing any of the above described methods in scheme I, II, III or IV toobtain the desired common intermediates of formula (10) and/or offormula (11).

Alternatively, the common intermediate of formula (11) can besynthesized by the process described in scheme VI.

In the above scheme VI wherein P, X, R¹, R²and R³ have the meaningsdescribed above the common intermediate (11) can be synthesized byformylation of intermediate (26) using standard formylation methods(dichloromethyl methylether in presence of tin chloride or titaniumchloride, POCl₃ in DMP, hexamethylenetetramine in TFA and the like)followed by oxidation (manganese or chromium reagents, sodium chlorite,potassium permanganate and the like) of the aldehyde group of formula(27) to the carboxylic acid group by conventional methods known in theliterature. The common intermediate (11) can also be synthesizeddirectly from the compound of formula (26) by standard carboxylationmethods (for example through sequential bromination, lithiation followedby treatment with carbon dioxide).

In another embodiment the compounds of formula (1) where Y is —SO₂NR⁴,can be synthesized using the process described in scheme VII.

In the above scheme VII wherein P, X, R¹, R²and R³ have the meaningsdescribed above the desired compounds of formula 1 can prepared bychlorosulfonylation using chlorosulfonic acid of the compound of formula(26) to obtain an intermediate of the formula (28) followed bysulfonamide formation by reacting intermediate (28) with the amine ofthe formula ArNHR⁴ using conventional methods such as using pyridine ordiisopropylethylamine or triethylamine in THF or dichloromethane and thelike. The desired compounds of formula (1) obtained are then convertedinto their salts and/or the N-oxides and, if desired, salts of thecompounds of formula (1) obtained are then converted into the freecompounds.

In yet another embodiment the compounds of formula (1) where Y is NR⁴SO₂can be synthesized using the process described in scheme VIII.

In the above scheme VIII wherein P, X, R¹, R², R³ and R⁴ have themeanings described above the desired compounds of formula 1 can preparedby nitration of the compound of formula (26) to obtain an intermediateof the formula (29) followed by reduction (raney nickel/hydrazine,iron/ammonium chloride, hydrogenation using Pd/C, and the like) of thenitro to amino group to obtain intermediate (30) using conventionalmethods. The intermediate (30) can be reacted with appropriate sulfonylchloride ArSO₂Cl to obtain the sulfonamide (31) which can alkylated tothe desired compounds of formula 1 using conventional methods like(sodium hydride or potassium carbonate in THF or DMF and the like ). Thesulfonamide( 31) is also one of the desired compounds wherein R⁴ ishydrogen.

The desired compounds of formula 1 obtained are then converted intotheir salts and/or the N-oxides and, if desired, salts of the compoundsof formula 1 obtained are then converted into the free compounds.

In yet another embodiment the compounds of formula 1 where Y is —NR⁴CO,can be synthesized using the process described in scheme IX

In the above scheme IX wherein P, X, R¹, R², R³ and R⁴ have the meaningsdescribed above the desired compounds of formula 1 can prepared bynitration using nitric acid in sulfuric acid, potassium nitrate insulfuric acid and the like, of the compound of formula (26) to obtain anintermediate of formula( 29)followed by reduction (raneynickel/hydrazine, iron/ammonium chloride, hydrogenation using Pd/C, andthe like) of the nitro to amino group to obtain intermediate (30) usingconventional methods. The intermediate (30) can be reacted with anappropriate acid chloride of the formula ArCOCl or appropriate mixedanhydride of the formula ArCOOCOR⁵ (R⁵ is alkyl, cycloalkyl, aryl,heteroaryl, heterocyclyl) to obtain the amide (32) which can alkylatedto the desired compounds of formula (1) using conventional methods. Theamide (32) is also one of the desired compounds wherein R⁴ is hydrogen.

The desired compounds of formula (1) obtained are then converted intotheir salts and/or the N-oxides and, if desired, salts of the compoundsof formula (1) obtained are then converted into the free compounds.

The N-oxidation is carried out in a manner likewise familiar to theperson of ordinary skill in the art, e.g with the aid ofm-chloroperoxybenzoic acid in dichloromethane at room temperature. Theperson of ordinary skill in the art is familiar with the reactionconditions which are necessary for carrying out the process on the basisof his knowledge.

The substances according to the invention are isolated and purified in amanner known per se, e.g. by distilling off the solvent in vacuum andrecrystallizing the residue obtained from a suitable solvent orsubjecting it to one of the customary purification methods, such ascolumn chromatography on a suitable support material.

Salts are obtained by dissolving the free compound in a suitablesolvent, e.g in a chlorinated hydrocarbon, such as methylene chloride orchloroform, or a low molecular weight aliphatic alcohol (ethanol,isopropanol) which contains the desired acid or base, or to which thedesired acid or base is then added. The salts are obtained by filtering,reprecepitating, precipitating with a non-solvent for the addition saltor by evaporating the solvent. Salts obtained can be converted bybasification or by acidifying into the free compounds which, in turn canbe converted into salts.

In general, the ethereal solvents used in the above described processesfor the preparation of compounds of the formula (1) are selected fromdiethyl ether, 1,2-dimethoxyethane, tetrahydrofuran, diisopropyl ether,1,4 dioxane and the like. The chlorinated solvent which may be employedmay be selected from dichloromethane, 1,2-dichloroethane, chloroform,carbontetrachloride and the like. The aromatic solvents which may beemployed may be selected from benzene and toluene. The alchoholicsolvents which may be employed may be selected from methanol, ethanol,n-propanol, iso propanol, tert-butanol and the like. The aproticsolvents which may be employed may be selected fromN,N-dimethylformamide, dimethyl sulfoxide and the like.

In general, the compounds prepared in the above described processes areobtained in pure form by using well known techniques such ascrystallization using solvents such as pentane, diethyl ether, isopropylether, chloroform, dichloromethane, ethyl acetate, acetone, methanol,ethanol, isopropanol, water or their combinations, or columnchromatography using alumina or silica gel and eluting the column withsolvents such as hexane, petroleum ether (pet.ether), chloroform, ethylacetate, acetone, methanol or their combinations.

Various polymorphs of a compound of general formula (1) forming part ofthis invention may be prepared by crystallization of compound of formula(1) under different conditions, example, using different solventscommonly used or their mixtures for recrystallization; crystallizationsat different temperatures, various modes of cooling, ranging from veryfast to very slow cooling during crystallizations. Polymorphs may alsobe obtained by heating or melting the compound followed by gradual orfast cooling. The presence of polymorphs may be determined by solidprobe NMR spectroscopy, IR spectroscopy, differential scanningcalorimetry, powder X-ray diffraction or such other techniques.

The present invention provides novel heterocyclic compounds, theiranalogs, their tautomers, their regioisomers, their stereoisomers, theirenantiomers, their diastreomers, their polymorphs, theirpharmaceutically acceptable salts, their appropriate N-oxides and theirpharmaceutically acceptable solvates.

The present invention also provides pharmaceutical compositions,containing compounds of general formula (1) as defined above, theirderivatives, their analogs, their tautomeric forms, their stereoisomers,their polymorphs, their enantiomers, their diasteromers, theirpharmaceutically acceptable salts or their pharmaceutically acceptablesolvates in combination with the usual pharmaceutically employedcarriers, diluents and the like. The pharmaceutical compositionsaccording to this invention can be used for the treatment of allergicdisorders.

It will be appreciated that some of the compounds of general formula (1)defined above according to the invention can contain one or moreasymmetrically substituted carbon atoms. The presence of one or more ofthese asymmetric centers in the compounds of general formula (1) cangive rise to stereoisomers and in each case the invention is to beunderstood to extend to all such stereoisomers, including enantiomersand diastereomers and their mixtures, including racemic mixtures. Theinvention may also contain E & Z geometrical isomers wherever possiblein the compounds of general formula (1) which includes the single isomeror mixture of both the isomers

The pharmaceutical compositions may be in the forms normally employed,such as tablets, capsules, powders, syrups, solutions, suspensions andthe like and may contain flavorants, sweeteners etc. in suitable solidor liquid carriers or diluents, or in suitable sterile media to forminjectable solutions or suspensions. The active compounds of formula (1)will be present in such pharmaceutical compositions in the amountssufficient to provide the desired dosage in the range as describedabove. Thus, for oral administration, the compounds of formula (1) canbe combined with a suitable solid, liquid carrier or diluent to formcapsules, tablets, powders, syrups, solutions, suspensions and the like.The pharmaceutical compositions, may, if desired, contain additionalcomponents such as flavorants, sweeteners, excipients and the like. Forparenteral administration, the compounds of the formula (1) can becombined with sterile aqueous or organic media to form injectablesolutions or suspensions. For example, solutions in sesame or peanutoil, aqueous propylene glycol and the like can be used as well asaqueous solutions of water-soluble pharmaceutically-acceptable acidaddition salts or salts with base of the compounds of formula (1) Theinjectable solutions prepared in this manner can then be administeredintravenously, intraperitoneally, subcutaneously, or intramuscularly,with intramuscular administration being preferred in humans.

The compounds can also be administered by inhalation when applicationwithin the respiratory tract is intended. Formulation of the presentcompounds is especially significant for respiratory inhalation, whereinthe compound of Formula (1) is to be delivered in the form of an aerosolunder pressure. It is preferred to micronize the compound of Formula (1)after it has been homogenised, e.g., in lactose, glucose, higher fattyacids, sodium salt of dioctylsulfosuccinic acid or, most preferably, incarboxymethyl cellulose, in order to achieve a microparticle size of 5μm or less for the majority of particles. For the inhalationformulation, the aerosol can be mixed with a gas or a liquid propellantfor dispensing the active substance. An inhaler or atomizer or nebulizermay be used. Such devices are known. See, e.g., Newman et al., Thorax,1985, 40_(—)61-676; Berenberg, M., J. Asthma USA, 1985, 22:87-92;incorporated herein by reference in their entirety. A Bird nebulizer canalso be used. See also U.S. Pat. Nos. 6,402,733; 6,273,086; and6,228,346, incorporated herein by reference in their entirety. Thecompound of the structure (1) for inhalation is preferably formulated inthe form of a dry powder with micronized particles. The compounds of theinvention may also be used in a metered dose inhaler using methodsdisclosed in U.S. Pat. No. 6,131,566, incorporated herein by referencein its entirety.

In addition to the compounds of formula (1) the pharmaceuticalcompositions of the present invention may also contain or beco-administered with one or more known drugs selected from otherclinically useful therapeutic agents.

The invention is explained in detail in the examples given below whichare provided by way of illustration only and therefore should not beconstrued to limit the scope of the invention.

The following intermediates are used to synthesize the rerpesentativeexamples of the compounds of the invention.

Intermediate 1: 3-(2-nitrophenoxy)-4-methoxy benzaldehyde

To a stirred suspension of potassium fluoride (5.71 gm, 0.0985 mol) indry DMSO (20 ml) was added a solution of isovanillin (10.0 gm, 0.0657mol) in DMSO (20 ml). The reaction contents were heated at 140° C. for10 min. A solution of 2-fluoronitrobenzene (9.27 gm, 0.0657 mol) in DMSO(10 ml) was added to the above suspension and the reaction mixture wasstirred at 140° C. for 3.5 h. The reaction mixture was cooled to roomtemperature and the contents were poured into water (200 ml) andextracted with ethyl acetate (100 ml×3). The organic extracts werecombined and washed with 1N sodium hydroxide (50 ml×2), water and brineand dried over anhydrous sodium sulfate. The dried organic layer wasconcentrated in vacuo to obtain the product as a pale yellow solid (13.6gm). IR (KBr) 2940, 2842, 2748, 1690, 1602, 1578, 1523, 1509, 1432,1345, 1285, 1117, 1017, 815, 737 cm⁻¹.

¹H NMR (300 MHz, CDCl₃) δ 3.91 (s, 3H), 6.9 (d, 1H, J=9.0 Hz), 7.11 (d,1H, J=9.0 Hz), 7.2 (t, 1H, J=7.8 Hz), 7.48 (t, 1H, J=7.8 Hz), 7.51 (s,1H), 7.71 (dd, 1H, J=7.8 Hz, 1.8 Hz), 7.95 (d, 1H, J=7.8 Hz,), 9.82 (s,1H).

Intermediate 2: 3-(2-nitrophenoxy)-4-methoxy-phenyl carboxylic acid

To a solution of intermediate 1 (10 gm, 0.036 mol) in acetone-watermixture in 4:1 ratio (75 ml) was added sulfamic acid (5.32 gm, 0.054mol) while stirring at 0° C. A solution of 80% sodium chlorite (3.4 gm,0.045 mol) in water (15.0 ml) was added dropwise to the above reactionmixture over a period of 10 min. and was allowed to stir at 0° C. foradditional 30 min. The precipitate obtained was filtered, washed withwater and air dried to give 12 gm of the product as white solid.

¹H NMR (300 MHz, CDCl₃) δ 3.8 (s, 3 H), 6.9 (d, 1H, J=9.0 Hz), 7.28 (t,1H, J=9.0 Hz), 7.30 (d, 1H, J=9.0 Hz), 7.56 (s, 1H), 7.6 (t, 1H, J=7.2Hz), 7.85 (d, 1H, J=8.4 Hz,), 8.02 (d, 1H, J=8.4 Hz).

Intermediate 3: 3-(2-amiophenoxy)-4-methoxyphenyl carboxylic acid

To a suspension of intermediate 2 (10 gm) in dichloromethane (500 ml)was added 5% Pd/C (10% w/w) and the mixture hydrogenated at 40 psi for 3h (hours) under hydrogen atmosphere. The catalyst was filtered overcelite. The celite bed was washed with methanol. The combined filtratewas concentrated in vacuo to yield the desired product as pale yellowsolid (8.5 gm).

IR KBr) 3450, 3368, 2925, 1683, 1601, 1578, 1501, 1438, 1307, 1276,1217, 1017, 788, 761 cm⁻¹.

¹H NMR (300 MHz, CDCl₃) δ 3.93 (s, 3 H), 6.63-6.68 (brm, 1 H), 6.75 (m,3 H), 6.91-7.0 (brm, 3H), 7.53 (s, 1 H), 7.80 (d, 1H, J=8.4 Hz).

Intermediate 4: 4methoxy dibenzo[b,d]furan-1-carboxylic acid

A suspension of intermediate 3 (2 gm, 0.0077 mol) in a mixture ofconcentrated hydrochloric acid:water (1:1) (20 ml) is warmed to 45° C.for 10 min. and cooled to −5° C. A solution of sodium nitrite (630 mg,0.0092 mol) in water (5 ml) is added dropwise to the above suspension at−5° C. The reaction mixture was stirred for 30 min and a chilledsolution of sodium fluoroborate (1.26 gm, 0.0115 mol) was added to theabove reaction mixture and stirred at −5° C. for 30 min. The diazoniumfluoroborate salt obtained (2.3 gm) as a result was filtered and washedwith 5% cold sodium fluoroborate solution and air dried. The drieddiazonium fluoroborate salt was added to a stirred suspension of cuprousoxide (1.76 gm, 0.0077 mol) in 0.1 N sulfuric acid (600 ml) at 35° C.and stirred for 10 min. The resulting precipitate (2.0 gm) was filtered,washed with water, air dried and chromatographed on silica gel columnusing 20% ethyl acetate in chloroform to give the desired product as awhite solid (200 mg); mp: 280° C.

IR (KBr) 2925, 2853, 1688, 1607, 1512, 1490, 1437, 1277, 1221, 1023,cm⁻¹.

¹H NMR (300 MHz, DMSO) δ 4.05 (s, 3 H), 7.26 (d, 1H, J=8.7 Hz), 7.40 (t,1H, J=7.2 Hz), 7.50 (t, 1H, J=7.2 Hz), 7.74 (d, 1H, J=8.1 Hz), 8.01 (d,1H, J=8.4 Hz), (8.85 (d, 1H, J=7.8 Hz).

Intermediate 5: 3-(2-nitro-4-trifluoromethyl phenoxy)-4-methoxybenzaldehyde

To a stirred suspension of potassium fluoride (457 mg, 7.8 mmol) in dryDMSO (20 ml) was added a solution of isovanillin (1.0 gm, 6.57 mmol) indry DMSO (20 ml). The reaction contents were heated at 140° C. for 10min. A solution of 4-fluoro-3-nitrobenzotrifluoride (1.37 gm, 6.57 mmol)in dry DMSO (10 ml) was added to the above suspension and the reactionmixture was stirred at 140° C. for 4.0 h. The reaction mixture wascooled to room temperature and the contents were poured into water (200ml) and extracted with ethyl acetate (100 ml×3). The organic extractswere combined and washed with 1N sodium hydroxide (50 ml×2), water andbrine and dried over anhydrous sodium sulfate. The organic layer wasconcentrated in vacuo to obtain 3-(2-nitro-4-trifluoromethylphenoxy)-4-methoxy benzaldehyde as a pale yellow solid (2.0 gm).

IR (KBr) 3098, 3031, 2953, 2745, 2649, 1694, 1629, 1606, 1540, 1509,1439, 1333, 1275, 1158, 1118, 1095, 1015, 912, 820cm⁻¹.

¹H NMR (300 MHz, CDCl₃) δ3.86 (s, 3H), 7.05 (d, 1H, J=8.7 Hz), 7.44 (d,1H, J=8.7 Hz), 7.77 (s, 1H), 7.92 (d, 2H, J=8.4 Hz), 8.45 (s, 1H), 9.87(s, 1H).

Intermediate 6: 3-(2-nitro-4-trifluoromethyl phenoxy)-4-methoxy-phenylcarboxylic acid

To a solution of intermediate 5 (10 gm, 0.036 mol) in acetone-watermixture in 4:1 ratio (75 ml) was added sulfamic acid (5.32 gm, 0.054mol) while stirring at 0° C. A solution of 80% sodium chlorite (3.4 gm,0.045 mol) in water (15.0 m1l) was added dropwise to the above reactionmixture over a period of 10 min. and was allowed to stir at 0° C. foradditional 30 min. The precipitate obtained was filtered, washed withwater and air dried to give 12 gm of the product as white solid. IR(KBr) 3445, 2944, 2568, 1694, 1629, 1609, 1542, 1517, 1442, 1334, 1289,1133, 1016, 766 cm⁻¹.

¹H NMR (300 MHz, CDCl₃) δ 3.87 (s, 3H), 6.88 (d, 1H, J=8.7 Hz), 7.10 (d,1H, J =8.7 Hz), 7.65 (dd, 1H, J=8.7 Hz, 1.8 Hz), 7.88 (d, 1H, J=1.8 Hz), 8.04 (dd, 1H, J=8.4, 1.8 Hz), 8.25 (d, 1H, J=1.8 Hz).

Intermediate 7: 3-(2-amino-4-trifluoromethyl phenoxy)-4-methoxy-phenylcarboxylic acid

To a suspension of intermediate 6 (10 gm ) in dichloromethane (500 ml)was added 5% Pd/C (10% w/w) and hydrogenated at 40 psi for 3 h underhydrogen atmosphere. The catalyst was filtered over celite. The celitebed was washed with methanol. The combined filtrate was concentrated invacuo to yield the desired product.

IR (KBr) 3452, 3367, 3063, 3006, 2937, 2842, 2545, 1692, 1625, 1611,1514, 1444, 1334, 1278, 1211, 1116, 1023, cm⁻¹.

¹H NMR (300 MHz, DMSO) δ3.85 (s, 3H), 5.5 (s, 2H), 6.6 (d, 1H), 6.8 (d,1H), 7.1 (s, 1H), 7.3 (d, 1H), 7.4 (d, 1H), 7.8 (s, 1H).

Intermediate 8: 4-methoxy-8-trifluoromethyldibenzo[b,d]furan-1-carboxylic acid

A suspension of intermediate 7 (2 gm, 0.0077 mol) in a mixture ofconcentrated hydrochloric acid:water (1:1) (20 ml) is warmed to 45° C.for 10 min. and cooled to −5° C. A solution of sodium nitrite (630 mg,0.0092 mol) in water (5 ml) is added dropwise to the above suspension at−5° C. The reaction mixture was stirred for 30 min and a chilledsolution of sodium fluoroborate (1.26 gm, 0.0115 mol) was added to theabove reaction mixture and stirred at −5° C. for 30 min. The diazoniumfluoroborate salt obtained (2.3 gm) as a result was filtered and washedwith 5% cold sodium fluoroborate solution and air dried. The drieddiazonium fluoroborate salt was added to a stirred suspension of cuprousoxide (1.76 gm, 0.0077 mol) in 0.1 N sulfuric acid (600 ml) at 35° C.and stirred for 10 min The resulting precipitate (2.0 gm) was filtered,washed with water, air dried and chromatographed on silica gel columnusing 20% ethyl acetate in chloroform to give the desired product as awhite solid was synthesized using the procedure described in step 4 ofexample 1 from 3-(2-amino-4-trifluoromethyl phenoxy)-4-methoxy-phenylcarboxylic acid.

IR (KBr) 3132, 3024, 2975, 2941, 2916, 2844, 2648, 2546, 1693, 1592,1575, 1421, 1328,1278,1154,1105,912,824 cm⁻¹.

¹H NMR (300 MHz, DMSO) δ 4.1 (s, 3H), 7.4 (d, 1H, J=8.4 Hz), 7.9 (d, 1H,J=8.7 Hz), 8.0 (d, 1H, J=8.7 Hz), 8.08 (d, 1H, J=8.7 Hz), 9.29 (s, 1H).

Intermediate 9: 3-(2-nitro-4-trifluoromethylphenoxy)-4-difluoromethoxybenzaldehyde

A solution of 4-difluoromethoxy-3-hydroxybenzaldehyde (2.0 gm, 10.63mmol) in DMSO (5 ml) was added to a stirred suspension of potassiumfluoride (0.740 gm, 12.76 mmol) in dry DMSO (10 ml). A solution of4-fluoro-3-nitrobenzotrifluoride (3.22 gm, 10.63 mmol) in DMSO (5 ml)was added to the above suspension and the reaction mixture was stirredat 160° C. for 18 h. The reaction mixture was cooled to room temperatureand the contents were poured into water (100 ml) and extracted withethyl acetate (25 ml×3). The organic extracts were combined and washedwith 1N sodium hydroxide (25 ml×2), water and brine and dried overanhydrous sodium sulfate. The dried organic layer was concentrated invacuo to obtain the product as a pale yellow solid (2.2 gm).

IR (KBr) 3092, 2878, 1697, 1629, 1537, 1352, 1331, 1280, 1158, 1134,1075, 827 cm⁻¹.

¹H NMR (300 MHz, DMSO) δ 7.23 (d, 1 H, J=8.7 Hz), 7.35 (t, 1 H, J=72.6Hz), 7.63 (d, 1H, J=8.1 Hz), 7.86 (d, 1 H, J=2.1 Hz), 7.93 (dd, 1H,J=8.4 Hz, 1.8 Hz), 7.99 (dd, 1H, J=8.7 Hz, 2.4 Hz ), 8.48 (d, 1H, J=2.4Hz), 9.94 (s, 1H).

Intermediate 10: 3-(2-nitro-4-trifluoromethylphenoxy)-4-difluoromethoxy-phenyl carboxylic acid

To a solution of intermediate 9 (10 gm, 0.036 mol) in acetone-watermixture in 4:1 ratio (75 ml) was added sulfamic acid (5.32 gm, 0.054mol) while stirring at 0° C. A solution of 80% sodium chlorite (3.4 gm,0.045 mol) in water (15.0 ml) was added dropwise to the above reactionmixture over a period of 10 min. and was allowed to stir at 0° C. foradditional 30 min. The precipitate obtained was filtered, washed withwater and air dried to give 12 gm of the product as white solid.

IR (KBr) 3436, 3095, 2997, 2889, 2665, 2566, 1695, 1633, 1545, 1447,1379, 1355, 1284, 1270, 1155, 1120, 1099, 1063, 917, 765 cm⁻¹.

¹H NMR (300 MHz, DMSO) δ 6.60 (t, 1 H, J=72.6 Hz), 6.96 (d, 1 H, J=8.7Hz), 7.44 (d, 1H, J=8.7 Hz), 7.55 (dd, 1 H, J=9.0 Hz, 1.8 Hz), 7.86 (d,1H, J=2.1 Hz), 8.04 (dd, 1H, J=8.4 Hz, 2.4 Hz), 8.27 (d, 1H, J=1.8 Hz),.

Intermediate 11:3-(2-amino-4-trifluoromethylphenoxy)-4-difluoromethoxy-phenyl carboxylicacid

To a suspension of intermediate 10 (10 gm ) in dichloromethane (500 ml)was added 5% Pd/C (10% w/w) and hydrogenated at 40 psi for 3 h underhydrogen atmosphere. The catalyst was filtered over celite. The celitebed was washed with methanol. The combined filtrate was concentrated invacuo to yield the desired product as pale yellow solid (8.5 gm).

IR (KBr) 3377, 2926, 1702, 1627, 1582, 1515, 1447, 1419, 1335, 1276,1198, 1116, 1064, 813, 786 cm⁻¹.

Intermediate 12: 4-difluoromethoxy-8-trifluoromethyldibenzo[b,d]furan-1-carboxylic acid

A suspension of intermediate 11 (2 gm, 0.0077 mol) in a mixture ofconcentrated hydrochloric acid:water (1:1) (20 ml) is warmed to 45° C.for 10 min. and cooled to −5° C. A solution of sodium nitrite (630 mg,0.0092 mol) in water (5 ml) is added dropwise to the above suspension at−5° C. The reaction mixture was stirred for 30 min and a chilledsolution of sodium fluoroborate (1.26 gm, 0.0115 mol) was added to theabove reaction mixture and stirred at −5° C. for 30 min. The diazoniumfluoroborate salt obtained (2.3 gm) as a result was filtered and washedwith 5% cold sodium fluoroborate solution and air dried. The drieddiazonium fluoroborate salt was added to a stirred suspension of cuprousoxide (1.76 gm, 0.0077 mol) in 0.1 N sulfuric acid (600 ml) at 35° C.and stirred for 10 min. The resulting precipitate (2.0 gm) was filtered,washed with water, air dried and chromatographed on silica gel columnusing 20% ethyl acetate in chloroform to give the desired product as awhite solid (200 mg); mp: 280° C.

IR (KBr) 3020, 2928, 2855, 1698, 1513, 1422, 1326, 1273, 1215, 1066,757, 669 cm⁻¹.

¹H NMR (300 MHz, DMSO) δ 6.57 (t, 1H, J=72.6 Hz) 7.03 (d, 1 H, J=8.4Hz), 7.58 (d, 1H, J=8.7 Hz), 7.93 (dd, 1H, J=8.4 Hz, 2.1 Hz), 8.18 (d,1H, J=8.4 Hz), 9.25 (s, 1H).

Intermediate 13: 3-(2-nitrophenoxy)-4-difluoromethoxy benzaldehyde

To a stirred suspension of potassium fluoride (372 mg, 6.4 mmol) in dryDMSO (10 ml) was added a solution of 3-hydroxy-4-difluoromethoxybenzaldehyde (1.0 gm, 5.3 mmol) in DMSO (10 ml). The reaction contentswere heated at 140° C. for 10 min. A solution of 2-fluoronitrobenzene(747 mg, 5.3 mmol) in DMSO (5 ml) was added to the above suspension andthe reaction mixture was stirred at 140° C. for 3.5 h. The reactionmixture was cooled to room temperature and the contents were poured intowater (200 ml) and extracted with ethyl acetate (100 ml×3). The organicextracts were combined and washed with 1N sodium hydroxide (50 ml×2),water and brine and dried over anhydrous sodium sulfite. The driedorganic layer was concentrated in vaccuo to obtain3-2-nitrophenoxy)-4-difluoromethoxy benzaldehyde as a pale yellow solid(1.4 gm).

IR (KBr) 2916, 1692, 1616, 1530, 1446, 1350, 1283, 1112, 1063, 845, 737cm⁻¹.

Intermediate 14: 3-(2-nitrophenoxy)-4-difluoromethoxy-phenyl carboxylicacid

To a solution of intermediate 13 (10 gm, 0.036 mol) in acetone-watermixture in 4:1 ratio (75 ml) was added sulfamic acid (5.32 gm, 0.054mol) while stirring at 0° C. A solution of 80% sodium chlorite (3.4 gm,0.045 mol) in water (15.0 ml) was added dropwise to the above reactionmixture over a period of 10 min and was allowed to stir at 0° C. foradditional 30 min. The precipitate obtained was filtered, washed withwater and air dried to give 12 gm of the product as white solid.

¹H NMR (300 MHz, CDCl₃) δ 6.64 (t, 1H, J=72 Hz), 6.98 (d, 1 H, J=8.4Hz), 7.28 (t, 1H, J=7.2 Hz), 7.39 (d, 1H, J=9.0 Hz), 7.55 (t, 1 H, J=7.2Hz), 7.65(d, 1H, J=1.8 Hz), 7.90 (d, 1H, J=9.0 Hz, ), 8.01 (d, 1H, J=8.1Hz, ).

Intermediate 15: 3-(2-aminophenoxy)-4-difluoromethoxy-phenyl carboxylicacid

To a suspension of intermediate 14 (10 gm ) in dichloromethane (500 ml)was added 5% Pd/C (10% w/w) and hydrogenated at 40 psi for 3 h underhydrogen atmosphere. The catalyst was filtered over celite. The celitebed was washed with methanol. The combined filtrate was concentrated invacuo to yield the desired product

IR (KBr) 3367, 2925, 1624, 1579, 1501, 1481, 1384, 1272, 1196, 1170,1052, 785 cm⁻¹.

Intermediate 16: 4-difluoromethoxy dibenzo[b,d]furan-1-carboxylic acid

A suspension of intermediate 15 (2 gm, 0.0077 mol) in a mixture ofconcentrated hydrochloric acid:water (1:1) (20 ml) is warmed to 45° C.for 10 min. and cooled to −5° C. A solution of sodium nitrite (630 mg,0.0092 mol) in water (5 ml) is added dropwise to the above suspension at−5° C. The reaction mixture was stirred for 30 min and a chilledsolution of sodium fluoroborate (1.26 gm, 0.0115 mol) was added to theabove reaction mixture and stirred at −5° C. for 30 min. The diazoniumfluoroborate salt obtained (2.3 gm) as a result was filtered and washedwith 5% cold sodium fluoroborate solution and air dried. The drieddiazonium fluoroborate salt was added to a stirred suspension of cuprousoxide (1.76 gm, 0.0077 mol) in 0.1 N sulfuric acid (600 ml) at 35° C.and stirred for 10 min. The resulting precipitate (2.0 gm) was filtered,washed with water, air dried and chromatographed on silica gel columnusing 20% ethyl acetate in chloroform to give the desired product.

¹H NMR (300 MHz, DMSO) δ 7.56 (t, 1H, J=72 Hz), 7.48 (m, 2 H), 7.64 (t,1H, J=8.1 Hz), 8.30 (d, 1H, J=8.7 Hz), 8.02 (d, 1 H, J=8.1 Hz), 8.80 (d,1H, J=7.8 Hz).

Intermediate 17: 4-Cyclopentyloxydibenzo[b,d]furan

Reaction of dibenzo[b,d]furan-4-ol (1 g, 5.43 mmol) with cyclopentylbromide (1.60 g, 10.86 mmol) in the presence of 60% sodium hydride (326mg, 8.12 mmol), gave 1.25 g (92%) of the product as viscous liquid, IR(neat) 2957, 2870, 1449, 1269, 1193 cm⁻¹. ¹H NMR (300 MHz, CDCl₃) δ1.57-1.72 (m, 2 H), 1.84-1.89 (m, 2 H), 1.93-2.04 (m, 4 H), 5.01(quint., 1 H), 6.97 (d, J=8.1 Hz, 1 H), 7.22 (t, J=7.9 Hz,1 H), 7.30 (t,J=8.1 Hz, 1 H), 7.45 (t, J=8.1 Hz, 1 H), 7.51 (d, J=7.8 Hz, 1 H), 7.60(d, J=8.2 Hz, 1 H),7.89(d, J=8.1 Hz, 1 H).

Intermediate 18: 4-Cyclopentyloxydibenzo[b,d]furan-1-carbaldehyde

Reaction of 4-cyclopentyloxydibenzo[b,d]furan (1.0 g, 3.96 mmol) withdichloromethylmethylether (456 mg, 3.96 mmol) in presence oftin(IV)chloride (1.55 g, 5.95 mmol), gave 350 mg (31.5%) of the productas white solid, IR (KBr)) 2960, 2730, 1686, 1565, 1276, 1099 cm⁻¹. ¹HNMR (300 MHz, CDCl₃) δ 1.64-1.75 (m, 2 H), 1.85-1.98 (m, 2 H), 2.03-2.09(m, 4 H), 5.11 (quint, 1 H), 7.07 (d, J=8.2 Hz, 1 H), 7.38 (t, J=7.9H, 1H), 7.52 (t, J=7.8 Hz, 1 H), 7.63 (d, J=8.4 Hz, 1 H), 7.77 (d, J=8.2 Hz,1 H), 8.95 (d, J=8.4 Hz, 1 H), 10.17 (s, 1 H).

Intermediate 19: 4-hydroxy dibenzo[b,d]furan-1-carbaldehyde

Intermediate 18 was heated in HBr (30-33%) in glacial acetic acid (25ml) at 50° C. for 7-8 h The reaction contents were poured in ice-waterand extracted with ethyl acetate. The organic layer was washed withsaturated sodium bicarbonate, and extracted with 10% sodium hydroxide(3×25 ml) solution. The aqueous layer was acidified with conc. HCl togive a white precipitate which was filtered and air dried to obtain thecrude product as a white solid (3.2 gm).

Intermediate 20: 4-cyclopropylmethoxy dibenzo[b,d]furan-carbaldehyde

Intermediate 19 (500 mg, 2.358 mmol) was dissolved in dry DMF (5 ml).Anhydrous potassium carbonate (650 mg, 4.716 mmol) was added to theabove solution and was stirred for 10 min. at 80° C. To this was addedcyclopropylmethyl bromide (500 mg, 3.537 mmol) and the reaction mixturewas stirred for 1 h. The reaction mixture was cooled to room temperatureand diluted with water (100 ml) and extracted with ethyl acetate (3×50ml). The organic extract was washed with water (50 ml) and brinesolution (25 ml) and dried over anhydrous sodium sulfate. Removal ofsolvent gave the product as a white solid (550 mg).

IR (KBr) 3110, 2890, 2865,1642, 1567, 1478, 1444, 1358, 1278, 1267,1206, 1038, 842, 657 cm⁻¹.

¹H NMR (300 MHz, DMSO) δ 0.452 (m,2H), 0.66 (m, 2H), 1.38 (m, 1H),δ 4.18(d, 2H, J=7.2 Hz), δ 7.35 (d, 1H, J=8.4 Hz), δ 7.44 (t,1H, J=7.2 Hz), δ7.62 (t,1H, J=8.1 Hz), δ 7.83 (d,1H, J=8.4 Hz), δ 8.1 (d,1H, J=8.4 Hz),δ 8.8.(d,1H, J=7.2 Hz), δ 10.15 (s,1H).

Intermediate 21: 4-cyclopropylmethoxy dibenzo[b,d]furan-1-carboxylicacid

To a solution of intermediate 20(500 mg, 1.879 mmol) in acetone-watermixture in 2:1 ratio (20 ml) was added sulfamic acid (280 mg, 2.818mmol) while stirring at 0° C. A solution of 80% sodium chlorite (200 mg,2.215 mmol) in water (5 ml) was added dropwise to the above reactionmixture over a period of 10 min. and was allowed to stir at roomtemperature for additional 5 h. The reaction was diluted with water (200ml) and extracted with ethyl acetate (3×100 ml). The organic extract waswashed with water (100 ml) and brine solution (50 ml) and dried overanhydrous sodium sulfate. The organic solvent was evaporated to give 500mg of the product as white solid.

IR (KBr) 3108, 2885, 2867, 1652, 1558, 1469, 1441, 1349, 1282, 1271,1204, 1032, 845, 655 cm⁻¹

¹H NMR (300 MHz, DMSO) δ 0.452 (m, 2H), 0.66 (m, 2H), 1.38 (m, 1H), 4.13(d, 2H, J=7.5 Hz), 7.20 (d, 1H, J=9.0 Hz), 7.44 (t, 1H, J=6.9 Hz), 7.6(t, 1H, J=8.1 Hz), 7.8 (d, 1H, J=8.4 Hz), 7.9 (d, 1H, J=7.8 Hz), 8.86(d, 1H, J=7.5 Hz).

Intermediate 22: 4-isopropyloxy dibenzo[b,d]furan-1-carbaldehyde

Intermediate 19 (500 mg, 2.358 mmol) was dissolved in dry DMF (5 ml).Anhydrous potassium carbonate (650 mg, 4.716 mmol) was added to theabove solution and was stirred for 10 min. at 80° C. To this was addedisopropyl bromide (431 mg, 3.537mmol) and the reaction mixture wasstirred for 4 hrs. The reaction mixture was cooled to room temperatureand diluted with water (100 ml) and extracted with ethyl acetate (3×50ml). The organic extract was washed with water (50 ml) and brinesolution (25 ml) and dried over anhydrous sodium sulfate. Removal ofsolvent gave the product as a white solid (600 mg).

Intermediate 23: 4-isopropyloxy dibenzo[b,d]furan-1-carboxylic acid

To a solution of intermediate 22(600 mg, 2.35 mmol) in acetone-watermixture in 2:1 ratio (20 ml) was added sulfamic acid (348 mg, 3.52 mmol)while stirring at 0° C. A solution of 80% sodium chlorite (232 mg, 2.58mmol) in water (5 ml) was added dropwise to the above reaction mixtureover a period of 10 min. and was allowed to stir at room temperature foradditional 2 h. The reaction was diluted with water (200 ml) andextracted with ethyl acetate (3×100 ml). The organic extract was washedwith water (100 ml) and brine solution (50 ml) and dried over anhydroussodium sulfate. The organic solvent was evaporated to give the productas white solid (600 mg).

Intermediate 24: 4-benzyloxy dibenzo[b,d]furan-1-carbaldehyde

Intermediate 19 (1 gm, 5.10 mmol) was dissolved in dry DMF (10 ml).Anhydrous potassium carbonate (1.05 gm, 7.65 mmol) was added to theabove solution and was stirred for 10 min. at 80° C. To this was addedbenzyl bromide (0.87 gm, 5.10 mmol) and the reaction mixture was stirredfor 2 h. The reaction mixture was cooled to room temperature and dilutedwith water (100 ml) and extracted with ethyl acetate (3×50 ml). Theorganic extract was washed with water (50 ml) and brine solution (25 ml)and dried over anhydrous sodium sulfate. Removal of solvent gave theproduct as a brown solid (1.4 gm).

Intermediate 25: 4-benzyloxy dibenzo[b,d]furan-1-carboxylic acid

To a solution of intermediate 24(1.4 gm, 4.89 mmol) in acetone-watermixture in 2:1 ratio (22 ml) was added sulfamic acid (711 mg, 7.33 mmol)while stirring at 6° C. A solution of 80% sodium chlorite (550 mg, 6.11mmol) in water (5 ml) was added dropwise to the above reaction mixtureover a period of 10 min. and was allowed to stir at room temperature foradditional 2 h. The reaction was diluted with water (200 ml) andextracted with ethyl acetate (3×100 ml). The organic extract was washedwith water (100 ml) and brine solution (50 ml) and dried over anhydroussodium sulfate. The organic solvent was evaporated to give the productas yellow solid (1.0 gm).

Intermediate 26: 2-Bromoisovanillin

Isovanillin (5 gm, 0.033 mol) was dissolved in glacial acetic acid (30ml). Anhydrous sodium acetate (5.4 gm) was added to the above solutionfollowed by powdered iron (0.15 gm). The system was flushed thoroughlywith nitrogen. A solution of bromine (5.79 gm, 0.0362 mol) in glacialacetic acid (10 ml) was added to the above stirred suspension at 105° C.over a period of 15 min. The reaction mixture was cooled and stirred atroom temperature for 45 min. The reaction mixture was poured intoaqueous 2% sodium bisulfite (200 ml) and stirred for 10 min. Theprecipitate was filtered washed with water (100 ml), and dried to obtain3.5 gm of 2-bromoisovanillin as white powder mp: (200-202° C.).

IR (KBr) 3233, 2990, 2891, 2844, 1669, 1593, 1564, 1494, 1463, 1286,1238, 1205, 1019, 987, 805, 786 cm⁻¹.

¹H NMR (300 MHz, CDCl₃) δ 3.99 (s, 3H), 6.13 (s, 1H), 6.89 (d, 1H, J=8.4Hz), 7.55 (d, 1H, J=8.4 Hz), 10.23 (s, 1H).

Intermediate 27: 2-Bromo-3-(p-nitrophenoxy)-4-methoxy benzaldehyde

To a stirred suspension of potassium fluoride (1.89 gm, 0.0326 mol) indry DMSO (10 ml) was added a solution of intermediate 26 (5.0 gm, 0.0217mol) in DMSO (10 ml). A solution of 4-fluoronitrobenzene (5.0 gm, 0.0260mol) in DMSO (5 ml) was added to the above suspension and the reactionmixture was stirred at 140° C. for 4 h. The reaction mixture was cooledto room temperature and the contents were poured into water (150 ml) andextracted with ethyl acetate (50 ml×3). The organic extracts werecombined and washed with 1N sodium hydroxide (25 ml×2), water and brineand dried over anhydrous sodium sulfate. The dried organic layer wasconcentrated in vacuo and the residue was purified by silica-gel columnchromatography using 20% ethyl acetate-petroleum ether as the eluent togive 2-bromo-3-(p-nitrophenoxy)-4-methoxy benzaldehyde as a pale yellowsolid(5.0 gm)mp: 132-140° C.

IR(KBr) 3084, 2874, 1689, 1584, 1506, 1486, 1348, 1285, 1253, 1234,1114, 1025, 848, 815,747 cm⁻¹.

¹H NMR (300 MHz, CDCl₃) δ 3.86 (s, 3H), 6.89 (d, 2H, J=7.2 Hz), 7.07 (d,1H, J=9.0 Hz), 7.92 (d, 1H, J=8.4 Hz), 8.17 (d, 2H, J=9.0 Hz), 10.24 (s,1H).

Intermediate 28: 4-methoxy-8-nitro-1-formyl dibenzo[b,d]furan

Intermediate 26 (3.5 gm, 0.0087 mol), anhydrous sodium carbonate (1.125gm, 0.0106 mol) and palladium (II) acetate (0.19 gm, 0.0008 mol), indimethylacetamide (15 ml) are heated and stirred under nitrogen at 170°C. for 2h. Water (90 ml) is added to the cooled reaction mixture. Theprecipitated solid is collected by filteration and washed with 5%hydrochloric acid followed by water. The product was obtained as ayellow solid (3.4 gm).

IR (KBr) 3115, 2925, 2856, 1682, 1609, 1576, 1522, 1343, 1295, 1076,846, 829 cm⁻¹.

¹H NMR (300 MHz, DMSO) δ 4.13 (s, 3H), 7.53 (d, 1 H, J=9.0 Hz), 8.01 (d,1H, J=9.0 Hz), 8.16 (d, 1H, J=9.0 Hz), 8.48 (dd, 1H, J=9.0 Hz, 3.0 Hz),9.79 (d, 1H, J=3.0 Hz), 10.1 (s, 1H).

Intermediate 29: 4-methoxy-8-nitro dibenzo[b,d]furan-1-carboxylic acid

Intermediate 28 (1.1 gm, 0.0034 mol) in acetone (5 ml) was heated to60-70° C. for 10 min. To the above suspension was added dropwise a hotsolution of potassium permanganate (1.07 gm, 0.0068 mol) inwater:acetone (1:3) (15 ml) for 10 min. The reaction was heated to60-70° C. for 10 min., cooled to room temperature and filtered. Theresidue washed with acetone and the filterate was extracted with 10%sodium hydroxide solution. Acidification, followed by filteration andwashing of the precipitate yielded4-methoxy-8-nitro-dibenzo[b,d]furan-1-carboxylic acid (0.6 gm) as whitesolid, mp: 178° C. (dec.)

IR (KBr) 3467, 2942, 1711, 1694, 1633, 1610, 1574, 1522, 1453, 1417,1344, 1278, 1069, 846, 826, 743 cm⁻¹.

¹H NMR (300 MHz, DMSO) δ 4.08 (s, 3H), 7.36 (d, 1 H, J=8.4 Hz), 7.98 (d,1H, J=9.0 Hz), 8.07 (d, 1H, J=8.4 Hz), 8.44 (dd, 1H, J=9.0 Hz, 2.7 Hz),9.79 (d, 1H, J=2.4 Hz).

Intermediate 30: 4-methoxy-8amino-dibenzo[b,d]furan-1-carboxylic acid

To a suspension of intermediate 29 (1.05 gm, 3.105 mmol) in methanol (20ml) was added activated raney nickel (300 mg, 30% w/w) and refluxed for1 h. Hydrazine hydrate (0.77 gm, 15.5 mmol) was added slowly to theabove suspension over a period of 30 min. The reaction mixture wasallowed to reflux under stirring for 30 min. Methanol was evaporated andaqueous ammonia solution (25-28%) was added to the residue to get aclear solution. The suspended raney nickel was filtered and thefilterate was acidified to get the product as a white solid (700 mg) mp:264-273° C.

IR (KBr): 3391, 2938, 1709, 1608, 1581, 1495, 1451, 1396, 1278, 1183,933, 786, 634 cm⁻¹

¹H NMR (300 MHz, DMSO) δ 4.01 (s, 3H), 6.81 (d, 1H, J=8.1 Hz), 7.14 (d,1H), 7.35 (d, 1H, J=8.1), 7.84 (d, 1H), 8.1 (s, 1H),

Intermediate 31: 4-methoxy-8-chloro-dibenzo[b,d]furan-1-carboxylic acid

Intermediate 29 (350 mg, 1.13 mmol) was suspended in mixture ofconcentrated hydrochloric acid:water (1:1) (5 ml) and stirred at 50° C.for 30 min. The suspension was cooled to 0° C. and a solution of sodiumnitrite (83 mg, 1.2 mmol) in water (2 ml) was added dropwise in 15 min.The reaction was stirred for 90 min. at 0-5° C. and then this suspensionwas added to a pre-cooled solution of CuCl (123 mg, 1.24 mmol) inconcentrated HCl (5 ml). The reaction was allowed to come to roomtemperature and further heated to 80-90° C. for 2 h. The reactionmixture was then poured into water (100 ml) and the solid was filteredand then purified by column chromatography using 20% ethylacetate-chloroform as the eluent to obtain 250 mg of the product aswhite solid; mp: 264-276° C.

IR (KBr): 3432, 2924, 2853, 1739, 1687, 1601, 1571, 1416, 1292, 1259,1107, 1017, 907, 810, 630 cm⁻¹

¹H NMR (300 MHz, DMSO) δ 4.05 (s, 3H), 7.29 (d, 1H, J=8.7 Hz), 7.64 (d,1H, J=8.7 Hz), 7.80 (d, 1H, J=8.7 Hz), 8.01 (d, 1H, J=9.0 Hz), 8.88 (s,1H), 13.16 (s, 1H).

Intermediate 32: 4-methoxy-8-bromo-dibenzo[b,d]furan-1-carboxylic acid

Intermediate 30 (500 mg, 1.62 mmol) was suspended in mixture ofconcentrated hydrochloric acid:water (1:1) (5 ml) and stirred at 50° C.for 30 min. The suspension was cooled to 0° C. and a solution of sodiumnitrite (118 mg, 1.72 mmol) in water (2 ml) was added dropwise in 15min. The reaction was stirred for 90 min. at 0-5° C. and then a chilledsolution of sodium fluoroborate (25 mg, 1.62 mmol) in water (4 ml) wasadded to the above suspension and stirred for 30 min. The solid wasfiltered rapidly and washed with 5% solution of sodium fluoroborate. Thevacuum dried solid (400 mg) was suspended in 47% HBr (5 ml) and cuprousbromide CuBr (512 mg, 1.78 mmol) was added. The reaction was heated toabout 80-90° C. for 2 h and then poured into water (100 ml). Theresulting solid was filtered, washed with water and vacuum dried andthen purified by column chromatography using 20% ethylacetate-chloroform as the eluent to obtain 120 mg of the product aswhite solid; mp: 275° C. (dec).

IR (KBr): 3069, 2957, 2924, 2853, 1685, 1598, 1414, 1384, 1292, 1259,1104, 1056, 978, 808, 728, 628 cm⁻¹

¹H NMR (300 MHz, DMSO) δ 4.06 (s, 3H), 7.29 (d, 1H, J=8.7 Hz), 7.74 (m,2H), 8.02 (d, 1H, J=8.7 Hz), 9.04 (s, 1H).

Intermediate 33: 4-methoxy-8-iodo-dibenzo[b,d]furan-1-carboxylic acid

Intermediate 30 (500 mg, 1.62 mmol) was suspended in mixture ofconcentrated hydrochloric acid:water (1:1) (5 ml) and stirred at 50° C.for 30 min. The suspension was cooled to 0° C. and a solution of sodiumnitrite (118 mg, 1.72 mmol) in water (2 ml) was added dropwise in 15min. The reaction was stirred for 90 min. at 0-5° C. and then a chilledsolution of sodium fluoroborate (25 mg, 1.62 mmol) in water (4 ml) wasadded to the above suspension and stirred for 30 min. The solid wasfiltered rapidly and washed with 5% solution of sodium fluoroborate. Thevacuum dried solid (400 mg) was suspended in a solution of potassiumiodide (400 mg, 2.23. eq.) in water (25 ml). The reaction was heated toabout 80-90° C. for 2 h, then diluted with water (100 ml) and extractedwith ethyl acetate. The ethyl acetate was evaporated and the resultingcrude solid was then purified by column chromatography using 20% ethylacetate-chloroform as the eluent to obtain 320 mg of the product aswhite solid; nip: 249° C.

IR (KBr): 3079, 2973, 2934, 2856, 1686, 1628, 1595, 1571, 1412, 1291,1209, 1104, 892, 722, 628 cm⁻¹

¹H NMR (300 MHz, DMSO) δ 3.97 (s, 3H), 7.09 (d, 1H, J=8.4 Hz), 7.47 (d,1H, J=9.0 Hz), 7.72 (d, 1H, J=8.7 Hz), 7.80 (d, 1H, J=8.4 Hz), 9.66 (s,1H).

Intermediate 34: 4-(2-nitrophenoxy)-3-methoxy benzaldehyde

To a stirred suspension of potassium fluoride (2.3 gm, 0.0395 mol) indry DMSO (15 ml) was added a solution of vanillin (5.0 gm, 0.0329 mol)in DMSO (15 ml). A solution of 2-fluoronitrobenzene (4.63 gm, 0.0329mol) in DMSO (15 ml) was added to the above suspension and the reactionmixture was stirred at 140° C. for 3.5 h. The reaction mixture wascooled to room temperature and the contents were poured into water (300ml) and extracted with ethyl acetate (100 ml×3). The organic extractswere combined and washed with 1N sodium hydroxide (50 ml×2), water andbrine and dried over anhydrous sodium sulfate. The dried organic layerwas concentrated in vacuo to obtain the product as a pale yellow solid(7.15 gm); mp: 70-77° C.

IR (KBr) 3064, 2982, 2821, 1692, 1588, 1531, 1355, 1238, 1161, 1024,863, 778 cm⁻¹.

¹H NMR (300 MHz, CDCl₃) δ 3.91 (s, 3 H), 6.97 (d, 1H, , J=8.4 Hz), 7.03(d, 1H, J=7.8 Hz), 7.25 (t, 1H, J=8.1 Hz), 7.43 (d, 1H, J=7.8 Hz), 7.52(t, 1H, J=7.8 Hz), 8.0 (d, 1 H, J=7.8 Hz), 9.90 (s, 1 H).

Intermediate 35: 4-(2-nitrophenoxy)-3-methoxy-phenyl carboxylic acid

To a solution of intermediate 34 (7.15 gm, 0.0262 mol) in acetone (60ml) was added sulfamic acid (3.81 gm, 0.0393 mol) while stirring at 0°C. A solution of 80% sodium chlorite (3.31 gm, 0.0366 mol) in water(15.0 ml) was added dropwise to the above reaction mixture over a periodof 10 min. and was allowed to stir at 0° C. for additional 30 min. Thereaction was diluted with 120 ml of water and stirred for 30 min. Theprecipitate obtained was filtered, washed with water and air dried togive 7.0 gm of the product as white solid; mp: 153-155° C.

IR (KBr): 3084, 2901, 2655, 1699, 1593, 1531, 1425, 1301, 1228, 1027,876, 760 cm⁻¹.

¹H NMR (300 MHz, CDCl₃) δ 3.89 (s, 3 H), 6.95 (d, 1H, J=8.4 Hz), 6.99(d, 1H, J=8.7 Hz). 7.25 (t, 1H, J=8.4 Hz), 7.50 (t, 1H, J=7.8 Hz),7.70-7.73 (m, 2H), 7.99 (d, 1H, J=7.8 Hz).

Intermediate 36: 4-(2-aminophenoxy)-3-methoxy-phenyl carboxylic acid

To a suspension of intermediate 35 (7.0 gm) in dichloromethane (500 ml)was added 5% Pd/C (10% w/w) and hydrogenated at 40 psi for 5 h underhydrogen atmosphere. The catalyst was filtered over celite. The celitebed was washed with methanol. The combined filtrate was concentrated invacuo to yield the desired product as white solid (5.68 gm); mp:192-194°C.

IR (KBr) 3391, 3285, 2914, 2587, 1705, 1590, 1501, 1458, 1276, 1205,1113, 1029, 836, 750cm⁻¹.

¹H NMR (300 MHz, CDCl₃) δ 3.98 (s, 3 H), 6.71-6.77 (brm, 2H), 6.82 (d,1H, J=7.8 Hz), 6.89 (d, 1H, J=7.8 Hz), 7.02 (t, 1H, J=7.8 Hz), 7.62 (d,1H, J=7.8 Hz), 7.67 (s, 1 H).

Intermediate 37: 4-methoxy dibenzo[b,d]furan-2-carboxylic acid

A suspension of intermediate 36 (5.1 gm, 0.0197 mol) in a mixture ofconcentrated hydrochloric acid:water (1:1) (50 ml) is warmed to 45° C.for 30 min. and cooled to −5° C. A solution of sodium nitrite (1.628 gm,0.0236 mol) in water (5 ml) is added dropwise to the above suspension at−5° C. The reaction mixture was stirred for 30 min and a chilledsolution of sodium fluoroborate (3.43 gm, 0.0315 mol) was added to theabove reaction mixture and stirred at −5° C. for 30 min. The diazoniumfluoroborate salt obtained as a result was filtered and washed with 5%cold sodium fluoroborate solution and air dried. The dried diazoniumfluoroborate salt was added to a stirred suspension of cuprous oxide(5.63 gm, 0.0394 mol) in 0.1 N sulfuric acid (1800 ml) at 35° C. andstirred for 15 min. The resulting precipitate was filtered, washed withwater, air dried and chromatographed on silica gel column using 5%methanol in chloroform to give the desired product as a white solid (700mg); mp: 229-240° C.

IR (KBr): 3066, 2919, 2850, 2590, 1686, 1588, 1413, 1348, 1276, 1195,1037, 835, 760, 744 cm⁻¹.

¹H NMR (300 MHz, DMSO) δ 4.06 (s, 3 H), 7.45 (t, 1H, J=7.2 Hz), 7.59 (t,1H, J=7.2 Hz), 7.68 (s, 1H), 7.78 (d, 1H, J=8.1 Hz), 8.27 (d, 1H, J=7.2Hz), 13.07 (brs, 1H).

Intermediate 38: 4-Methoxydibenzo[b,d]furan

A solution of dibenzo[b,d]furan-4-ol (5 g, 27.1 mmol) in DMF (5 ml) wasadded to a stirred and cooled (0° C.) suspension of 60% sodium hydride(1.62 g, 40.62 mmol) in DMF (20). The mixture was stirred at 0° C. for 5min and methyl iodide (7.71 g, 54.34 mmol) in DMF (5 ml) was addeddropwise over a period of 10 min. The cooling bath was removed and themixture was stirred for 1 h at room temperature. The reaction mixturewas diluted with ice-cold water (100 ml) and extracted with EtOAc (3×50ml). The combined organic extracts were washed with water (2×100 ml),brine (100 ml) and dried (Na₂SO₄). The product obtained afterevaporation of the solvent was purified by silica gel columnchromatography using 5% ethyl acetate in petroleum ether to give 5.1 g(95 %) of the product as a low melting solid, mp 45-47° C.

IR (KBr) 3053, 2968, 2838, 1451, 1272, 1196, 1095 cm⁻¹;

¹H NMR (300 MHz, CDCl₃) δ 4.06 (s, 3 H), 6.98 (d, J=8.5 Hz, 1 H), 7.26(t, J=8.2 Hz, 1 H), 7.33 (t, J=8.2 Hz, 1 H), 7.45 (t, J=8.2 Hz, 1 H),7.54 (d, J=8.4 Hz, 1 H), 7.60 (d, J=8.5 Hz, 1 H), 7.93 (d, J=8.4 Hz, 1H).

Intermediate 39: 1-nitro-4-methoxy-dibenzo[b,d]furan

Intermediate 38 (1.0 gm, 5 mmol) was dissolved in glacial acetic acid(15 ml) and to this was added concentrated nitric acid (10 ml) at 20-25°C. in 10 min. The reaction was stirred for 2 h then poured into coldwater (200 ml). The resulting yellow solid was filtered and washed with5% sodium bicarbonate solution and purified through silica gel columnusing 5% ethyl acetate-petroleum ether to give 600 mg of pure product;mp: 130-132° C.

IR (KBr): 3086, 2926, 1631, 1588, 1571, 1513, 1448, 1321, 1300, 1280,1209, 1129, 1096, 1008, 987, 814, 742 cm⁻¹.

¹H NMR (300 MHz, DMSO) δ 4.12 (s, 3 H), 7.38 (d, 1H, J=8.7 Hz), 7.53 (t,1H, J=7.8 Hz), 7.69 (t, 1H, J=7.8 Hz), 7.84 (d, 1H, J=8.1 Hz), 8.32 (d,1H, J=9.0 Hz), 8.56 (d, 1H, J=9.0 Hz).

Intermediate 40: 1-amino-4-methoxy-dibenzo[b,d]furan

Intermediate 38 (550 mg, 2.26 mmol) was taken in methanol (10 ml) andraney nickel catalyst (100 mg, 18% w/w) was added. The reaction mixturewas refluxed and to this was added hydrazine hydrate (99%) solution (2ml) slowly over a period of 10 min. The refluxing continued for 2 h. Thecatalyst was filtered and the filterate was concentrated and dilutedwith water (100 ml) and further extracted with ethyl acetate (3×25 ml).The organic layer was washed with water and concentrated to give theproduct as brown solid (500 mg);mp:167-169° C.

¹H NMR (300 MHz, DMSO) δ 3.84 (s, 3 H), 5.37 (s, 2H), 6.50 (d,1H, J=9.0Hz), 6.90 (d, 1H, J=9.0 Hz), 7.32 (t, 1H, J=6.0 Hz), 7.40 (t, 1H, J=6.0Hz), 7.61 (d, 1H, J=7.5 Hz), 8.20 (d, 1H, J=7.8 Hz).

Intermediate 41: 4-ethoxycarbomethoxy dibenzo[b,d]furan-1-carbaldehyde

Intermediate 19 (500 mg, 2.358 mmol) was dissolved in dry DMF (5 ml).Anhydrous potassium carbonate (650 mg, 4.716 mmol) was added to theabove solution and was stirred for 10 min. at 80° C. To this was addedethylbromoacetate (2.0 eq.) and the reaction mixture was stirred for 1h. The reaction mixture was cooled to room temperature and diluted withwater (100 ml) and extracted with ethyl acetate (3×50 ml). The organicextract was washed with water (50 ml) and brine solution (25 ml) anddried over anhydrous sodium sulfate. Removal of solvent gave the productas a white solid (550 mg).

Intermediate 42: 4-ethoxycarbomethoxy dibenzo[b,d]furan-1-carboxylicacid

To a solution of intermediate 41(500 mg) in acetone-water mixture in 2:1ratio (20 ml) was added sulfamic acid (280 mg, 2.818 mmol) whilestirring at 0° C. A solution of 80% sodium chlorite (200 mg, 2.215 mmol)in water (5 ml) was added dropwise to the above reaction mixture over aperiod of 10 min. and was allowed to stir at room temperature foradditional 5 h. The reaction was diluted with water (200 ml) andextracted with ethyl acetate (3×100 ml). The organic extract was washedwith water (100 ml) and brine solution (50 ml) and dried over anhydroussodium sulfate. The organic solvent was evaporated to give the productas white solid.

Intermediate 43: 4-methoxy dibenzo[b,d]furan-3-carbaldehyde

Intermediate 38 (3.7 gm, 0.0186 mol) was dissolved in dichloromethane(30 ml) and the solution was cooled to 0° C. Tin (IV) chloride (8.3 gm,0.0317 mol) was added all at once to the above solution followed by thedropwise addition of 1,1-dichloromethyl methyl ether (2.2 gm, 0.0186mol). The reaction was stirred and allowed to come to room temperaturein 1 h. The reaction mixture was cooled in ice-bath and quenched withice water (25 ml) with vigorous stirring followed by extraction withchloroform (2×100 ml). The chloroform layer was washed with water (3×50ml) and dried over anhydrous sodium sulphate. Removal of solvent undervacuo gave the crude product a off-white solid (3.4 gm) which wasmixture of 4-methoxy dibenzo[b,d]furan-1-carbaldehyde and 4-methoxydibenzo[b,d]furan-3-carbaldehyde (80:20). Both the isomers wereseparated by silica gel coloumn chromatography using 20% ethyl acetatein petroleum ether as eluent to give 4-methoxydibenzo[b,d]furan-3-carbaldehyde as a white solid (500 mg); mp: 178-180°C.

IR (KBr): 2925, 2847, 1660, 1626, 1597, 1453, 1395, 1255, 1199, 1092,1005, 820, 754 cm⁻¹.

¹H NMR (300 MHz, DMSO) δ 4.36 (s, 3 H), 7.46 (t, 1H, J=7.2 Hz), 7.63 (t,1H, J=7.2 Hz), 7.71 (d, 1H, J=9.0 Hz), 7.81 (d, 1H, J=9.0 Hz), 7.92 (d,1H, J=7.8 Hz), 8.23 (d, 1H,J=7.8 Hz), 10.41 (s, 1H).

Intermediate 44: 4-methoxy dibenzo[b,d]furan-3-carboxylic acid

To a solution of intermediate 43 (250 mg, 1.106 mmol) in acetone-watermixture in 2:1 ratio (15 ml) was added sulfamic acid (130 mg, 1.327mmol) while stirring at 0° C. A solution of 80% sodium chlorite (150 mg,1.659 mmol) in water (5 ml) was added dropwise to the above reactionmixture over a period of 10 min. and was allowed to stir at roomtemperature for additional 1 h. The reaction was diluted with water (100ml) and extracted with ethyl acetate (3×25 ml). The organic extract waswashed with water (50 ml) and brine solution (50 ml) and dried overanhydrous sodium sulfate. The organic solvent was evaporated to give 200mg of the product as white solid; mp: 208-209° C.

IR (KBr): 2940, 2830, 2692, 1677, 1632, 1598, 1574, 1442, 1414, 1301,1198, 1091, 1001, 937, 780, 746 cm⁻¹.

¹H NMR (300 MHz, DMSO) δ 4.11 (s, 3 H), 7.44 (t, 1H, J=7.2 Hz), 7.59 (t,1H, J=7.2 Hz), 7.67 (d, 1H, J=8.4 Hz), 7.77 (d, 1H, J=7.8 Hz), 7.88 (d,1H, J=8.4 Hz), 8.18 (d, 1H, J=8.4 Hz).

Intermediate 45: 4-cyclopentoxy-3-hydroxy-benzaldehyde

A suspension of 3,4-dihydroxybenzaldehyde (5.0 gm, 0.0362 mol),anhydrous potassium carbonate (6.0 gm, 0.0434 mol) and cyclopentylbromide (6.5 gm, 0.0434 mol) in dry DMF (50 ml) was heated and stirredat 80° C. for 24 hrs. Reaction mixture was then cooled and diluted withwater (500 ml), acidified with 1N HCl and extracted with ethyl acetate(3×100 ml). The ethyl acetate extract was washed 5% sodium bicarbonateand brine and dried over anhydrous sodium sulfate. The dried extract onconcentration afforded a residue which was purified by silica gelchromatography using 10% ethyl acetate in petroleum ether as the eluentto provide 5.0 gm of the title product as white solid. mp: 87-89° C.

IR (KBr) 2964, 1670, 1605, 1580, 1500, 1463, 1358, 1271, 1122, 976, 806,748 cm⁻¹

¹H NMR (300 MHz, CDCl₃) δ 1.65-2.04 (m, 8H), 4.93 (m, 1H), 5.83 (s, 1H),6.94 (d, 1H), 7.38-7.43 (m, 2H), 9.82 (s, 1H).

Intermediate 46: 2-bromo-4-cyclopentoxy-3-hydroxy-benzaldehyde

Intermediate 45 (1.0 gm, 4.84 mmol) was dissolved in glacial acetic acid(20 ml). Anhydrous sodium acetate (0.8 gm, 9.7 mmol) was added to theabove solution followed by powdered iron (0.022 gm). The system wasflushed thoroughly with nitrogen. A solution of bromine (0.854 gm, 5.32mmol) in glacial acetic acid (10 ml) was added to the above stirredsuspension at 15° C. over a period of 15 min. The reaction mixture wasstirred at 15° C. for 45 min. The reaction mixture was poured intoaqueous 2% sodium bisulfite (100 ml) and stirred for 10 min. Theprecipitate was filtered washed with water (100 ml), and dried to obtain800 mg of 2-bromo-4-cyclopentoxy-3-hydroxy-benzaldehyde as white powdermp: 107-109° C.

¹H NMR (300 MHz, CDCl₃) δ 1.66-2.03 (m, 8H), 4.92 (m, 1H), 6.15 (s, 1H),6.90 (d, 1H), 7.54 (d, 1H), 10.25 (s, 1H).

Intermediate 47: 2-bromo-4-cyclopentoxy-3-(p-nitrophenoxy)-benzaldehyde

To a stirred suspension of potassium fluoride (125 mg, 2.104 mmol) indry DMSO (2.5 ml) was added a solution of intermediate 46 (500 mg, 1.754mmol) in DMSO (2.5 ml). A solution of 4-fluoronitrobenzene (500 mg,2.631 mmol) in DMSO (2.5 ml) was added to the above suspension and thereaction mixture was stirred at 140° C. for 6 h. The reaction mixturewas cooled to room temperature and the contents were poured into water(100 ml) and extracted with ethyl acetate (50 ml×3). The organicextracts were combined and washed with 1N sodium hydroxide (25 ml×2),water and brine and dried over anhydrous sodium sulfate. The driedorganic layer was concentrated in vacuo to give2-bromo-3-(p-nitrophenoxy)-4-methoxy benzaldehyde as a pale yellow solid(500 mg) mp:1.15-117° C.

¹H NMR (300 MHz, CDCl₃) δ 1.18-1.23 (m, 2H), 1.39-1.53 (m, 4H),1.73-1.81 (m, 2H), 5.01 (m, 1H), 7.09 (dd, 2H), 7.43 (d, 1H), 7.87 (d,1H), 8.24 (dd, 2H), 10.13 (s, 1H).

Intermediate 48: 4-cyclopentyloxy-8-nitro-1-formyl dibenzo[b,d]furan

Intermediate 47 (500 mg, 1.09 mmol), anhydrous sodium carbonate (150 mg,1.325 mmol) and palladium (II) acetate (25 mg, 0.096 mmol), indimethylformamide (10 ml) are heated and stirred under nitrogen at 130°C. for 7 h. Water (90 ml) is added to the cooled reaction mixture andextracted with ethyl acetate (2×25 ml). The combined organic layer waswashed with 5% hydrochloric acid followed by water and dried overanhydrous sodium sulfate to afford the product as a yellow solid (200mg). mp: 230-240° C.

¹H NMR (300 MHz, DMSO) δ 1.70 (m, 2H), 1.77-1.92 (m, 4H), 2.09 (m, 2H),5.25 (m, 1H), 7.53 (d, 1H), 8.05 (d, 1H), 8.14 (d, 1H, 8.51 (d, 1H),9.80 (s, 1H), 10.14 (s, 1H).

Intermediate 49: 4-hydroxy-8-nitro-1-formyl dibenzo[b,d]furan

Intermediate 48 (200 mg, 0.530 mol) was heated in HBr (47% in aceticacid) (5 ml) in glacial acetic acid (10 ml) at 50° C. for 7-8 h. Thereaction contents were poured in ice-water (200 ml) and extracted withethyl acetate (3×50 ml). The combined organic layer was washed withsaturated sodium bicarbonate, and water and dried over anhydrous sodiumsulfate. Removal of the organic solvent in vacuo afforded the crudeproduct as a white solid (150 mg). The crude white solid was used assuch without further purification. mp:>270° C.

¹H NMR (300 MHz, DMSO) δ 7.28 (d, 1H), 8.01 (d, 1H), 8.04 (d, 1H), 8.50(d, 1H), 9.83 (s, 1H), 10.09 (s, 1H), 11.92 (s, 1H).

Intermediate 50: 4-difluoromethoxy-8-nitro-1-formyl dibenzo[b,d]furan

A suspension of intermediate 49 (150 mg, 0.485 mmol) and anhydrouspotassium carbonate (200 mg, 1.455 mmol) in dry DMF (5.0 ml) was stirredat 80° C. for 10 min. Chlorodifluoromethane gas was purged into thereaction mixture for 45 min. The reaction mixture was cooled, dilutedwith water (50 ml), and extracted with ethyl acetate (3×25 ml). Thecombined organic layer was washed with water and dried over anhydroussodium sulfate. Removal of the organic solvent in vacuo afforded theproduct as a white solid (150 mg). mp: 245-248° C.

Intermediate 51: 4-difluoromethoxy-8-nitrodibenzo[b,d]furan-1-carboxylic acid

Intermediate 50 (150 mg, 0.48 mmol) in acetone (20 ml) and water (5 ml)was heated to 60-70° C. for 10 min. To the above solution was addeddropwise a solution of potassium permanganate (150 mg, 0.973 mmol) inwater (5 ml) for 10 min. The reaction was heated to 60-70° C. for 30min., and filtered hot through celite bed. Acidification of thefilterate resulted in a precipitate which on filteration and washingwith water yielded4-difluoromethoxy-8-nitro-dibenzo[b,d]furan-1-carboxylic acid (100 mg)as white solid; mp:>270° C.

¹H NMR (300 MHz, DMSO) δ 7.61 (t, 1H, J=72 Hz), 7.60 (d, 1H), 8.07 (d,1H), 8.13 (d, 1H), 8.52 (d, 1H), 9.77 (s, 1H), 13.80 (s, 1H).

Intermediate 52: 4-Ethoxydibenzo[b,d]furan

A solution of Dibenzo[b,d]furan-4-ol (1 g, 5.43 mmol) in DMF (5 ml) wasadded to a stirred and cooled (0° C.) suspension of 60% sodium hydride(326 mg, 8.12 mmol) in DMF (20 ml). The mixture was stirred at 0 ° C.for 5 min and ethyl iodide (1.18 g, 10.86 mmol) in DMF (5 ml) was addeddropwise over a period of 10 min. The cooling bath was removed and themixture was stirred for 1 h at room temperature. The reaction mixturewas diluted with ice-cold water (100 ml) and extracted with EtOAc (3×50ml). The combined organic extracts were washed with water (2×100 ml),brine (100 ml) and dried (Na₂SO₄), to give 0.95 g (82%) of the productas viscous liquid,

IR (neat) 3058, 2980, 1449, 1272, 1193 cm⁻¹;

¹H NMR (300 MHz, CDCl₃) δ 1.55 (t, J=7.2 Hz, 3 H), 4.29 (q, J=7.2 Hz, 2H), 6.96 (d, J=8.4 Hz, 1 H), 7.23 (t, J=8.0 Hz, 1 H), 7.30-7.52 (m, 3H), 7.61 (d, J=8.3 Hz, 1 H), 7.90 (d, J=8.4 Hz, 1 H).

Intermediate 53: 4-Cyclopropylmethoxydibenzo[b,d]furan

A solution of Dibenzo[b,d]furan-4-ol (1 g, 5.43 mmol) in DMF (5 ml) wasadded to a stirred and cooled (0° C.) suspension of 60% sodium hydride(326 mg, 8.12 mmol) in DMF (20 ml). The mixture was stirred at 0 ° C.for 5 min and cyclopropylmethyl bromide (1.31 g, 10.85 mmol) in DMF (5ml) was added dropwise over a period of 10 min. The cooling bath wasremoved and the mixture was stirred for 1 h at room temperature. Thereaction mixture was diluted with ice-cold water (100 ml) and extractedwith EtOAc (3×50 ml). The combined organic extracts were washed withwater (2×100 ml), brine (100 ml) and dried (Na₂SO₄), to give 1.16 g(90%) of the product as viscous liquid

IR (neat) 3080, 2923, 1449, 1273, 1192 cm⁻¹;

¹H NMR (300 MHz, CDCl₃) δ 0.44-0.49 (m, 2 H), 0.70-0.77 (m, 2 H),1.44-1.52 (m, 1 H), 4.10 (d, J=6.9 Hz, 2 H), 6.99 (d, J=8.1 Hz, 1 H),7.25 (t, J=7.5 Hz,1 H), 7.35 (t, J=8.4 Hz, 1 H), 7.47 (t, J=8.4 Hz, 1H), 7.55 (d, J=7.2 Hz, 1 H), 7.65 (d, J=8.1 Hz, 1 H, 7.94 (d, J=8.1 Hz,1 H).

Intermediate 54: Dibenzo[b,d]furan-4-yl methyl sulfide

To a stirred and cooled (−40° C.) solution of dibenzofuran (5 g, 29.76mmol) in dry THF (50 ml) was added 15% n-butyllithium in hexane (20 ml,46.87 mmol) in 5 min. The mixture was allowed to warm to roomtemperature in 20 min and further stirred at room temperature for 2 h.The brown solution was again cooled to −40° C. and sulfur powder (1.04g, 32.50 g atom) was added in one portion and maintained at the sametemperature for 1 h under stirring. Methyl iodide (5.5 g, 38.73 mmol)was then added drop-wise over a period of 10 min. The cooling bath wasremoved after 30 min and the mixture was stirred at room temperature for18 h. The reaction mixture was diluted with ice-cold water (100 ml) andextracted with EtOAc (2×100 ml). The combined organic extracts werewashed with water (3×100 ml), brine (100 ml) and dried Na₂SO₄). Theproduct obtained after evaporation of the solvent was purified by silicagel column chromatography using 5% ethyl acetate in petroleum ether togive 4.5 g (70%) of the product as viscous yellow liquid;

IR (KBr) 3054, 2919, 1448, 1407, 1196, 1182 cm⁻¹;

¹H NMR (300 MHz, CDCl₃) δ 2.64 (s, 3 H), 7.27-7.38 (m, 3 H), 7.46 (t,J=7.6 Hz, 1 H), 7.62 (d, J=7.8 Hz, 1 H), 7.77 (d, J=7.8 Hz, 1 H), 7.94(d, J=7.8 Hz, 1 H).

Intermediate 55: 4-Ethoxydibenzo[b,d]furan-1-carbaldehyde

To a stirred solution of intermediate 52 (850 mg, 4.01 mmol) in drydichloromethane (10 ml) was added tin) chloride(1.56 g, 6.0 mmol) in oneportion followed by drop-wise addition of dichloromethylmethyl ether(460 mg, 4.01 mmol) in dichloromethane (5 ml). The mixture wasmaintained at 0° C. for a period of 20 min and the dark mixture wasquenched by the addition of ice-cold water (50 ml). The aqueous layerwas extracted with dichloromethane (20 ml) and the combined organiclayer was washed with water (2×25 ml) and brine (25 ml). The crudeproduct obtained after evaporation of the solvent was purified by silicagel column chromatography using 25% ethyl acetate in petroleum ether togive 260 mg (21%) of the product as white solid, mp 92-94° C.;

IR (KBr) 2986, 2936, 1686, 1567, 1281, 1099 cm⁻¹;

¹H NMR (300 MHz, CDCl₃) δ 1.62 (t, J=7.2 Hz, 3 H), 4.40 (q, J=7.2 Hz, 2H), 7.09 (d, J=8.4 Hz, 1 H), 7.40 (t, J=7.2 Hz, 1 H), 7.53 (t, J=7.2 Hz,1 H), 7.65 (d, J=8.2 Hz, 1 H), 7.80 (d, J=8.4 Hz, 1 H), 8.97 (d, J=7.2Hz, 1 H), 10.18 (s, 1 H).

Intermediate 56: 4-Cyclopropylmethoxydibenzo[b,d]furan-1-carbaldehyde

To a stirred solution of intermediate 53(1.0 g, 4.2 mmol) in drydichloromethane (10 ml) was added tin(IV)chloride (1.6 g, 6.30 mmol) inone portion followed by drop-wise addition of dichloromethylmethylether(485 mg, 4.2 mmol) in dichloromethane (5 ml). The mixture was maintainedat 0° C. for a period of 20 min and the dark mixture was quenched by theaddition of ice-cold water (50 ml). The aqueous layer was extracted withdichloromethane (20 ml) and the combined organic layer was washed withwater (2×25 ml) and brine (25 ml). The crude product after evaporationof the solvent gave 120 mg (10.8%) of the product as white solid, mp93-95° C.;

IR (KBr) 2929, 2850, 2729, 1682, 1568, 1280, 1098 cm⁻¹.

¹H NMR (300 MHz, CDCl₃) δ 0.45-0.50 (m, 2 H), 0.72-0.79 (m, 2 H),1.41-1.51 (m, 1 H), 4.14 (d, J=7.2 Hz, 1 H), 7.04 (d, J=8.4 Hz, 1 H),7.37 (t, J=7.2 Hz, 1 H), 7.54 (t, J=7.2 Hz, 1 H), 7.65 (d, J=8.2 Hz, 1H), 7.76 (d, J=8.4 Hz, 1 H), 8.96 (d, J=8.0 Hz, 1 H), 10.17 (s, 1 H).

Intermediate 57: 4-Methylsulfanyldibenzo[b,d]furan-1-carbaldehyde

To a vigorously stirred and cooled (0° C.) solution of intermediate 54(4 g, 18.89 mmol) and dichloromethylmethyl ether (3.26 g, 28.36 mmol) indry dichloromethane (80 ml) was added titanium(IV)chloride (10.64 g,56.08 mmol) in one portion. After 1 h, the ice bath was removed and thedark brown mixture was quenched by the addition of ice-cold water (200ml). The layers were separated and the aqueous layer was extracted withdichloromethane (200 ml). The combined organic extracts were washed withwater (2×100 ml), brine (100 ml) and dried (Na₂SO₄). The productobtained after evaporation of the solvent was purified by silica gelcolumn chromatography using 20% ethyl acetate in petroleum ether to give2.0 g (40%) of the product as white solid, mp 130-133° C.;

IR (KBr) 2923, 2849, 1685, 1586, 1557, 1371, 1058 cm⁻¹;

¹H NMR (300 MHz, DMSO-d₆) δ 2.75 (s, 3 H), 7.46 (t, J=7.1 Hz, 1 H),7.58-7.66 (m, 2 H), 7.82 (d, J=7.2 Hz, 1 H), 8.02 (d, J=7.2 Hz, 1 H),8.88 (d, J=7.2 Hz, 1 H), 10.24 (s, 1 H).

Intermediate 58: 4Ethoxydibenzo[b,d]furan-1-carboxylic acid

To a stirred and cooled (° C.) solution of intermediate 55 (240 mg, 1.0mmol) and sulphamic acid (135 mg, 1.5 mmol) in acetone (5 ml) was addedaqueous sodium chlorite (126 mg, 1.30 mmol) over a period of 5 minutes.The mixture was warmed to room temperature and allowed to stir at roomtemperature for 3 h. The mixture was diluted with water (15 ml) andextracted with EtOAc (3×20 ml). The combined organic extracts werewashed with water (30 ml), brine (30 ml) and dried (Na₂SO₄). The crudeproduct obtained after evaporation of the solvent was purified bycrystallization from chloroform-hexane to give 180 mg (70%) of theproduct as white solid, mp 254-256° C.;

IR (KBr) 3434, 2982-2540 (br), 1681, 1283, 1094 cm⁻¹;

¹H NMR (300 MHz, DMSO-d₆ δ 1.47 (t, J=6.9 Hz, 3 H), 4.34 (q, J=6.9 Hz, 2H), 7.23 (d, J=8.4 Hz, 1 H), 7.40 (t, J=7.2 Hz, 1 H), 7.57 (t, J=7.2 Hz,1 H), 7.76 (d, J=8.1 Hz, 1 H), 7.97 (d, J=8.4 Hz, 1 H), 8.85 (d, J=8.1Hz, 1 H).

Intermediate 59: 4-Cyclopropylmethoxydibenzo[b,d]furan-1-carboxylic acid

To a stirred and cooled (° C.) solution of intermediate 56 (100 mg, 0.37mmol) and sulphamic acid (51 mg, 0.56 mmol)in acetone (5 ml) was addedaqueous sodium chlorite (50 mg, 048 mmol) over a period of 5 minutes.The mixture was warmed to room temperature and allowed to stir at roomtemperature for 3 h. The mixture was diluted with water (15 ml) andextracted with EtOAc (3×20 ml). The combined organic extracts werewashed with water (30 ml), brine (30 ml) and dried (Na₂SO₄). The crudeproduct obtained after evaporation of the solvent gave 75 mg (71%) ofthe product as off-white solid;

IR (KBr) 2998-2538 (br), 1682, 1570, 1278, 1093 cm⁻¹;

¹H NMR (300 MHz, DMSO-d₄) δ 0.40-0.45 (m, 2 H), 0.62-0.68 (m, 2 H),1.33-1.39 (m, 1 H), 4.13 (d, J=6.9 Hz, 1 H), 7.22 (d, J=8.4 Hz, 1 H),7.40 (t, J=8.1 Hz,1 H), 7.58 (t, J=7.2 Hz, 1 H), 7.79 (d, J=8.1 Hz, 1H), 7.96 (d, J=8.4 Hz, 1 H), 8.85 (d, J=8.4 Hz, 1 H), 13.02 (brs, 1 H).

Intermediate 60: 4-Cyclopentyloxydibenzo[b,d]furan-1-carboxylic acid

To a stirred and cooled (° C.) solution of intermediate 18 (300 mg, 1.06mmol) and sulphamic acid (160 mg, 1.6 mmol) in acetone (5 ml) was addedaqueous sodium chlorite (140 mg, 1.36 mmol) over a period of 5 minutes.The mixture was warmed to room temperature and allowed to stir at roomtemperature for 3 h. The mixture was diluted with water (15 ml) andextracted with EtOAc (3×20 ml). The combined organic extracts werewashed with water (30 ml), brine (30 ml) and dried (Na₂SO₄). The crudeproduct obtained after evaporation of the solvent gave 220 mg (69.4%) ofthe product as white solid, mp 233-235° C.;

IR (KBr) 3435, 2969-2543 (br), 1674, 1278, 1093 cm⁻¹;

¹H NMR (300 MHz, DMSO-d₆) δ 1.57-1.65 (m, 2 H), 1.75-1.88 (m, 2 H),1.93-1.97 (m, 4 H), 2.50 (brs, 1 H), 4.99 (quint., J=3.9 Hz, 1 H), 6.89(d, J=8.7 Hz, 1 H), 7.23 (t, J=8.3 Hz, 1 H), 7.38 (t, J=8.3 Hz, 1 H),7.52 (d, J=8.6 Hz, 1 H), 7.95 (d, J=8.7 Hz, 1H), 8.85 (d, J=8.6 Hz, 1H).

Intermediate 61: 4-Methylsulfanyldibenzo[b,d]furan-1-carboxylic acid

To a stirred and cooled (° C.) solution of intermediate 57 (1 g, 4.13mmol) and sulphamic acid (800 mg, 8.26 mmol) in acetone (5 ml) was addedaqueous sodium chlorite (600 mg 6.63 mmol) over a period of 5 minutes.The mixture was warmed to room temperature and allowed to stir at roomtemperature for 3 h. The mixture was diluted with water (15 ml) andextracted with EtOAc (3×20 ml). The combined organic extracts werewashed with water (30 ml), brine (30 ml) and dried (Na₂SO₄). The crudeproduct obtained after evaporation of the solvent gave 1 g (93%) of theproduct as white solid, mp 250-253° C.;

IR (KBr) 3421 (br), 2970-2540, 1709, 1379, 1264, 1008 cm⁻¹;

¹H NMR (300 MHz, DMSO-d₆) δ 3.01 (s, 3 H), 7.49 (t, J=7.5 Hz, 1 H), 7.63(t, J=7.5 Hz, 1 H), 7.82 (d, J=8.1 Hz, 1 H), 7.93 (d, J=8.1 Hz, 1 H),8.19 (d, J=8.1 Hz, 1 H), 8.80 (d, J=8.0 Hz, 1 H).

Intermediate 62: N-Formyl-1-methoxy-9H-carbazole

In a 50 mL round bottomed flask was dissolved POCl₃ (0.6 mL, 15.23 mM)in 20 mL of dry DMF. The reaction mixture was stirred at 0° C. in an icebath. To this was added slowly, 1-methoxy-9H-carbazole (1 g, 5.07 mM)dissolved in 30 mL of dry DMF. The reaction mixture was stirred for 2hrs. Water was added to the reaction mixture and the precipitatedproduct was filtered off. The residue was dissolved in EtOAc and waswashed with brine and dried over anh. Na₂SO₄. Ethyl acetate was thenevaporated to obtain the desired product as a white fluffy solid with ayield of 96% (1.1 g); mp 161-163° C.

¹H NMR (d6-DMSO, 300 MHz) δ 4.02 (3H, s), 7.22 (1H, d, J=7.8 Hz), 7.36(1H, t, J=8.1 Hz), 7.43 (1H, d of t, J=7.5 Hz, J=0.9 Hz), 7.52 (1H, d oft, J=7.5 Hz, J=0.9 Hz), 7.77 (1H, d, J=7.2 Hz), 8.14 (1H, d, J=7.8 Hz),8.51 (1H, d, J=8.1 Hz), 10.14 (1H, s).

IR (Neat): 1683, 1429, 1339, 1266, 1139, 743 cm⁻¹.

Intermediate 63: N-Formyl-1-methoxy-4-chlorosulphonyl-9H-carbazole

In a 50 mL round bottomed flask was taken 0.5 g of thionyl chloride and2 g of chlorosulphonic acid. To it was added intermediate 62 (1 g, 4.44mM) keeping the temperature below 25° C. The reaction mixture turnedblack. 1 ml of thionyl chloride was added and the reaction mixture wasstirred at room temperature for 3 hrs. It was then quenched with ice andwater. The white solid formed was extracted with ethylacetate and theorganic layer was washed with water, brine and dried over anh. Na₂SO₄.It was then evaporated to obtain the desired compound as a beige colorsolid with a yield of 63% (0.91 g); mp201-203° C.

¹H NMR (d₆-DMSO, 300 MHz) δ 4.04 (3H, s), 7.17 (1H, d, J=8.7 Hz), 7.36(1H, d of t, J=8.1 Hz, J=1.2 Hz), 7.49 (1H, d of t, J=8.1 Hz, J=1.2 Hz),7.77 (1H, d, J=8.4 Hz), 8.54 (1H, d, J=8.1 Hz), 9.11 (1H, d, J=7.5 Hz),10.26 (1H, s).

IR (KBr): 1693, 1567, 1453, 1393, 1358, 1306, 1278, 1167, 1141 cm⁻¹.

Intermediate 64: 9-tetrahydro-2H-2-pyranyl-9H-carbazole

To a stirred solution of carbazole (20.0 gm, 0.119 moles) in drychloroform (300 ml) at 0° C., D-10 camphor sulphonic acid (5% W/W, 1.0gm) was added followed by a solution of 3,4-dihydro 2H-pyran (0.149moles, 13.6 ml) in dry chloroform (50 ml) dropwise over a period of 30min. The reaction mixture was gradually warmed to room temperature andstirred at the same temperature for 2 hours. The reaction mixture wasdiluted with chloroform (400 ml) and washed with a solution of saturatedNaHCO₃ (150 ml), followed by water (150 ml), dried over Na₂SO₄ andconcentrated to give 31 gm of crude material which was recrystallisedfrom 500 ml of iso-propanol to give 24 gm of the title product as whitecrystalline powder, m. p: 131-133° C.

IR (KBr, cm⁻¹): 3435, 2949, 1594, 1482, 1451, 1334, 1044 and 751.

¹H NMR (300 MHz, CDCl₃, δ): 1.7-1.8 (m, 1H), 1.8-2.0 (m, 3H), 2.1-2.2(m, 1H), 2.4-2.6 (m, 1H), 3.8-3.9 (t, J=11.0 Hz, 1H), 4.3-4.4 (d, J=12.0Hz, 1H), 5.75-5.85 (d, J=12.0 Hz, 1H), 7.2-7.3 (t, J=6.5 Hz, 2H),7.4-7.5 (t, J=6.4 Hz, 2H), 7.6-7.7 (d, J=8.1 Hz, 2H), 8.1-8.2 (d, J=8.2Hz, 2H).

Intermediate 65: 1-hydroxy 9-tetrahydro-2H-2-pyranyl-9H-carbazole

To a stirred solution of intermediate 64 (20 gm, 0.0796 moles) in sodiumdried hexane (2400 ml) at room temperature, 1.6 M n-BuLi (0.175 moles,110 ml) was added dropwise and the reaction mixture was stirred at thesame temperature for 15 hours. The mixture was then refluxed for 4hours, dry THF (250 ml) was added to it, cooled to 0° C. and dry oxygengas was passed through the mixture for 5 hours. To the reaction mixture,1N HCl (200 ml) was added, stirred for 10 minutes and the layers wereseparated. The aqueous layer was then extracted with ethyl acetate (300ml). The organic layers were mixed, washed with brine (300 ml), driedover Na₂SO₄ and concentrated to give 24 gm of crude material which wasthen purified by column chromatography to give 7.0 gm of the titleproduct as pale yellow solid, m. p: 137-140° C.

IR (KBr, cm⁻¹): 3191, 2927, 1580, 1453, 1329, 1238, 1029 and 755.

¹H NMR (300 MHz, CDCl₃, δ): 1.7-2.0 (m, 4H), 2.0-2.15 (m, 2H), 4.0 (t,J=12.0 Hz, 1H), 4.5 (d, J=12.0 Hz, 1H), 5.8-5.9(d, J=12.0 Hz, 1H),7.0-7.1 (t, J=8.4 Hz, 1H), 7.2 (t, J=6.4 Hz, 2H),7.4 (t, J=6.1 Hz, 2H),7.6-7.7 (d, J=8.1 Hz, 1H), 8.08-8.1 (d, J=8.4 Hz, 1H), 9.05 (s, 1H).

Intermediate 66: 1-methoxy 9-tetrahydro-2H-2-pyranyl-9H carbazole

To a stirred solution of intermediate 65 (3.0 gm, 11 mmoles) in dry DMF(45 ml), at 0° C., sodium hydride (60% suspension, 0.64 gm, 14 mnoles)was added in portions and the reaction mixture was stirred at roomtemperature for 1 hour. The reaction mixture was cooled to 0° C., methyliodide (1.05 ml, 16 mmoles) was added to it dropwise and the mixture wasstirred at room temperature for 1 hour. The reaction mixture was pouredon to ice-water (100 ml), 1N HCl (50 ml) was added and extracted withethyl acetate (2×75 ml). The organic layer was washed with water (3×50ml) followed by brine (50 ml), dried over Na₂SO₄ and concentrated togive 3.4 gm of the title product as a thick liquid.

IR (Neat, cm⁻¹): 3400, 2927, 1579, 1455, 1440, 1336, 1262, 1040 and 743.

¹H NMR (300 MHz, CDCl₃, δ): 1.7-1.8 (m, 1H), 1.8-2.0 (m, 3H), 2.0-2.1(m, 1H), 2.4-2.5 (m, 1H), 3.8 (t, J=11.0 Hz, 1H), 4.0 (s, 3H), 4.3 (d,J=12.0 Hz, 1H), 6.6-6.7(d, J=12.0 Hz, 1H),6.9-7.0 (d, J=7.5 Hz,1H),7.1-7.15 (t, J=7.5 Hz, 1H), 7.15-7.2 (t, J=7.5 Hz, 1H), 7.3-7.4 (t,J=8.4 Hz, 1H), 7.6-7.7 (d, J=7.5 Hz, 2H), 7.9-8.0 (d, J=8.4 Hz, 1H),8.0-8.1 (d, J=8.4 Hz, 2H).

Intermediate 67: 1-Methoxy 9H-carbazole

To a stirred solution of intermediate 66 (3.4 gm, 12.08 mmoles) in THF(40 ml), 6N HCl (40 ml) was added and the reaction mixture was refluxedfor 2 hours. Solvent was evaporated from the reaction mixture underreduced pressureor and extracted with ethyl acetate (2×40 ml). Theorganic layer was washed with brine (40 ml), dried over Na₂SO₄ andconcentrated to give 2.9 gm of the title product as a thick liquid.

IR (Neat, cm⁻¹): 3422, 2925, 1579, 1456, 1258, 1024 and 743.

¹H NMR (300 MHz, DMSO-d₆, δ): 4.0 (s, 3H), 6.9-7.0 (d, J=7.5 Hz, 1H),7.0-7.1 (d, J=7.5 Hz, 1H), 7.1-7.2 (t, J=6.9 Hz, 1H), 7.3-7.4 (t, J=6.0Hz, 1H), 7,4-7.5 (t, J=8.1 Hz, 1H), 7.6-7.7 (d, J=7.8 Hz, 1H), 8.0 (d,J=7.5Hz, 1H), 11.2 (s, 1H)

Intermediate 68: 1-Methoxy 9H-9-carbazole carbaldehyde

To a stirred solution of intermediate 67 (2.9 gm, 15.21 mmoles) in dryDMF (30 ml) at 0° C., phosphorous oxychloride (4.25 ml, 45.64 mmoles)was added dropwise and the reaction mixture was allowed to stir at roomtemperature for 30 min. The reaction mixture was poured in to water (50ml) and extracted with ethyl acetate (3×50 ml). The organic layer waswashed with water (3×50 ml) followed by brine (50 ml), dried over Na₂SO₄and concentrated to give 2.5 gm of the title product as brown crystalinesolid, m.p: 143-148° C. (dec).

IR (Neat, cm⁻¹): 3469, 3019, 1691, 1589, 1430, 1266, 1215 and 757.

¹H NMR (300 MHz, CDCl₃, δ): 4.0 (s, 3H), 7.0-7.1 (d, J=7.8 Hz, 1H),7.3-7.4 (t, J=8.4 Hz, 1H), 7.4-7.5 (t, J=8.1 Hz, 1H), 7.5-7.6 (t, J=8.1Hz, 1H), 7.6-7.7 (d, J=7.5 Hz, 1H), 7.9-8.0 (d, J=7.5 Hz, 1H), 8.6-8.7(d, J=7.8Hz, 1H), 10.3 (s, 1H)

Intermediate 69: 4-bromo-1-methoxy 9H-9-carbazole carbaldehyde

To a stirred solution of intermediate 68 (2.5 gm, 11.1 mmoles) inglacial acetic acid (25 ml) at 0° C., a solution of bromine (0.6 ml,11.6 mmoles) in glacial acetic acid (10 ml) was added dropwise and thereaction mixture was stirred at the same temperature for 30 min. Thereaction mixture was poured in to water (50 ml), stirred for 10 min. andthe separated solid was filtered. The solid was washed with water (3×100ml) and dried to give 3.1 gm of the title product as brown crystallinesolid, m. p: 142-144° C. (dec).

IR (KBr, cm⁻¹): 3374, 2926, 1695, 1575, 1448, 1392, 1262, 1013 and 759.

¹H NMR (300 MHz, DMSO-d₆, δ): 4.0 (s, 3H), 7.2 (d, J=8.7 Hz, 1H),7.5-7.6 (t, J=6.6 Hz, 1H), 7.6 (d, J=8.7 Hz, 1H), 7.6-7.7 (t, J=7.2 Hz,1H), 8.6-8.7 (d, J=8.4 Hz, 1H), 8.7 (d, J=7.5 Hz, 1H), 10.2 (s, 1H).

Intermediate 70: 4-bromo-1-methoxy 9H-carbazole

To a stirred solution of intermediate 69(0.6 gm, 1.97 mmoles) in ethanol(10 ml), aqueous 6M NaOH soln.(3.5 ml) was added and the reactionmixture was refluxed for 1 hour. Ethanol was evaporated from thereaction mixture under reduced pressure and extracted with ethyl acetate(2×30 ml). The organic layer was washed with water (2×20 ml), dried overNa₂SO₄ and concentrated to give 0.5 gm of the title product as a thickliquid.

IR (Neat, cm⁻¹): 3463, 2933, 2848, 1573, 1497, 1454, 1402, 1287, 1254,1099, 1014 and 757.

¹H NMR (300 MHz, DMSO-d₆, δ): 4.0 (s, 3H), 6.9-7.0 (d, J=7.8 Hz, 1H),7.2-7.3 (t, J=7.4 Hz, 1H), 7.3 (d, J=7.8 Hz, 1H), 7.4-7.5 (t, J=7.4 Hz,1H), 7.5-7.6 (d, J=8.1 Hz, 1H), 8.5 (d, J=8.1 Hz, 1H), 11.7 (s, 1H).

Intermediate 71: 1-methoxy 9H-4-carbazole carbaldehyde

To a stirred solution of intermediate 70 (0.5 gm, 1.81 mmoles) in sodiumdried ether (20 ml) at room temperature, 2.5 M n-BuLi (5.43 mmoles) wasadded dropwise and the reaction mixture was stirred at the sametemperature for 2 hours. The reaction mixture was cooled to 0° C. anddry DMF (0.42 ml, 5.43 mmoles) was added and the reaction mixture wasstirred at room temperature for 2 hours. Ice pieces were added to thereaction mixture followed by 1N HCl (10 ml) and extracted with ethylacetate (2×15 ml). The organic layer was washed with brine (15 ml),dried over Na₂SO₄ and concentrated to give 0.5 gm of crude materialwhich was purified by column chromatography, to give 0.35 gm of thetitle compound as an off white solid, m. p: 173-177° C. (dec).

IR (KBr, cm⁻¹): 3246, 1657, 1553, 1290,- 1167 and 739.

¹H NMR (300 MHz, DMSO-d₆, δ): 4.2 (s, 3H), 7.1-7.2 (d, J=6.0 Hz, 1H),7.3 (d, J=8.1 Hz, 1H), 7.5 (t, =6.0 Hz, 1H), 7.6 (d, J=8.1 Hz, 1H), 7.9(d, J=8.4 Hz, 1H), 9.0 (d, J=8.1 Hz, 1H),10.2 (s, 1H), 11.8 (s, 1H).

Intermediate 72: 1-methoxy 9H-4-carbazole carboxylic acid

To a solution of intermediate 71 (0.3 gm, 1.333 mmoles) in a 2:1 mixtureof acetone and water (15 ml) at 0° C., sulphamic acid (0.259 gm, 2.666mmoles) was added followed by a solution of sodium chlorite (0.181 gm,2.0 mmoles) in water (5 ml) and the reaction mixture was stirred at roomtemperature for 2 hours. Acetone was evaporated from the reactionmixture under reduced pressure and extracted with ethyl acetate (2×25ml). The organic layer was washed with brine (25 ml), dried over Na₂SO₄and concentrated to give 0.3 gm of crude material which was purified bycolumn chromatography, to give 0.25 gm of the title compound as palebrown solid, m. p: 216-218° C. (dec).

IR (KBr, cm⁻¹): 3461, 2927, 1682, 1566, 1421, 1294, 1263, 1096, 1011 and741.

¹H NMR (300 MHz, DMSO-d₆, δ): 4.21(s, 3H), 7.0-7.1 (d, J=8.4 Hz, 1H),7.1-7.2 (t, J=7.2 Hz, 1H), 7.4 (t, J=7.5 Hz, 1H), 7.5 (d, J=8.1 Hz, 1H),7.8 (d, J=8.4 Hz, 1H), 8.9 (d, J=8.1 Hz, 1H),11.6(s, 1H), 12.6(s, 1H).

Intermediate 73: 1-methoxy 9H-4-carbazole carboxylicacid methyl esterderivatives

To a solution of intermediate 71 (0.3 gm, 1.333 mmoles) in a 2:1 mixtureof acetone and water (15 ml) at 0° C., sulphamicacid (0.259 gm, 2.666mmoles) was added followed by a solution of sodium chlorite (0.181 gm,2.0 mmoles) in water (5 ml) and the reaction mixture was stirred at roomtemperature for 2 hours. Acetone was evaporated from the reactionmixture under reduced pressureor and extracted with ethyl acetate (2×25ml). The organic layer was washed with brine (25 ml), dried over Na₂SO₄and concentrated to give 0.3 gm of crude material which was suspended indry chloroform (15 ml), under nitrogen atmosphere, thionyl chloride (0.3ml, 4.0 mmoles) was added followed by two drops of dry DMF and thereaction mixture was stirred at room temperature for 2 hours. Drymethanol (15 ml) was added to the reaction mixture and continued thestirring for 10 min. The reaction mixture was adsorbed on silica gel andpurified by column chromatography to get the desired products as givenbelow.

Intermediate 73a: 1-methoxy 9H-4-carbazole carboxylicacid methyl ester

IR (KBr, cm⁻¹): 3326, 2927, 1694, 1623, 1569, 1434, 1299, 1262, 1012,753 and 646.

¹H NMR (300 MHz, DMSO-d₆, δ): 3.94 (s, 3H), 4.065(s, 3H), 7.063-7.091(d, J=8.4 Hz, 1H), 7.112-7.165 (t, J=7.5 Hz, 1H), 7.377-7.427 (t, J=7.5Hz, 1H), 7.510-7.537 (d, J=8.1 Hz, 1H), 7.8-7.83 (d, J=8.4 Hz, 1H),8.77-8.8 (d, J=8.1 Hz, 1H),11.69 (s, 1H).

Intermediate 73b: 6 chloro-1-methoxy 9H-4-carbazole carboxylicacidmethyl ester

¹H NMR (300 MHz, DMSO-d₆, δ): 3.94 (s, 3H), 4.07 (s, 3H), 7.11-7.138 (d,J=8.1 Hz, 1H), 7.419-7.455 (d, J=10.8 Hz, 1H), 7.52-7.547 (d, J=7.5 Hz,1H), 7.86-7.887 (d, J=8.4 Hz, 1H), 8.894-8.901 (d, J=2.1 Hz, 1H), 11.91(s, 1H).

Intermediate 73c: 8 chloro-1-methoxy 9H-4-carbazole carboxylicacidmethyl ester

¹H NMR (300 MHz, DMSO-d₆, δ): 3.94 (s, 3H), 4.08 (s, 3H), 7.13-7.19 (m,2H), 7.49-7.52 (d, J=9.0 Hz, 1H), 7.86-7.887 (d, J=8.4 Hz, 1H),8.763-8.79 (d, J=8.1 Hz, 1H), 11.79 (s, 1H).

Intermediate 74: 1-ethoxy 9-tetrahydro-2H-2-pyranyl-9H-carbazole

To a stirred solution of intermediate 65 (3.0 gm, 11 mmoles) in dry DMF(45 ml), at 0° C., sodium hydride (60% suspension, 0.64 gm, 14 mmoles)was added in portions and the reaction mixture was stirred at roomtemperature for 1 hour. The reaction mixture was cooled to 0° C., ethyliodide (1.05 ml, 16 mmoles) was added to it dropwise and the mixture wasstirred at room temperature for 1 hour. The reaction mixture was pouredon to ice-water (100 ml), 1N HCl (50 ml) was added and extracted withethyl acetate (2×75 ml). The organic layer was washed with water (3×50ml) followed by brine (50 ml), dried over Na₂SO₄ and concentrated togive 3.4 gm of the title product as a thick liquid.

IR (Neat, cm⁻¹): 3400, 2927, 1579, 1455, 1440, 1336, 1262, 1040 and 743.¹H NMR (300 MHz, CDCl₃, δ): 1.7-1.8 (m, 1H), 1.8-2.0 (m, 3H), 2.0-2.1(m, 1H), 2.4-2.5 (m, 1H), 3.8 (t, J=11.0 Hz, 1H), 4.0 (s, 3H), 4.3 (d,J=12.0 Hz, 1H), 6.6-6.7(d, J=12.0 Hz, 1H), 6.9-7.0 (d, J=7.5 Hz,1H),7.1-7.15 (t, J=7.5 Hz, 1H), 7.15-7.2 (t, J=7.5 Hz, 1H), 7.3-7.4 (t,J=8.4 Hz, 1H), 7.6-7.7 (d, J=7.5 Hz, 2H), 7.9-8.0 (d, J=8.4 Hz, 1H),8.0-8.1 (d, J=8.4 Hz, 2H).

Intermediate 75: 1-ethoxy 9H-carbazole

To a stirred solution of intermediate 74 (6.2 gm, 20.99 mmoles) in THF(30 ml), 6N HCl (30 ml) was added and the reaction mixture was refluxedfor 3 hours. Solvent was evaporated from the reaction mixture underreduced pressure and extracted with ethyl acetate (3×40 ml). The organiclayer was washed with brine (40 ml), dried over Na₂SO₄ and concentratedto give 4.4 gm of the title product as a thick liquid.

IR (Neat, cm⁻¹): 669, 755, 929, 1039, 1215, 1257, 1389, 1456, 1507,1581, 2400, 2942, 3019, and 3473.

¹H NMR (300 MHz, DMSO-d₆, δ): 1.714-1.763 (t,J=6.9 Hz, 3H), 4.194-4.262(q,J=6.9 Hz 2H), 6.918-6.943 (d, J=7.5 Hz, 1H), 7.009-7.060 (t, J=7.7Hz, 1H), 7.076-7.126 (t, J=7.3 Hz, 1H), 7.297-7.351 (t, J=7.4 Hz, 1H),7.456-7.482 (d, J=7.8 Hz, 1H), 7.628-7.654 (d, J=7.8 Hz, 1H),8.009-8.033 (d, J=7.2 Hz, 1H),11.153 (s,1H).

Intermediate 76: 1-ethoxy 9H-9-carbazole carbaldehyde

To a stirred solution of intermediate 75 (4.4 gm, 20.83 mmoles) in dryDMF (30 ml) at 0° C., phosphorous oxychloride (5.9 ml, 62.50 mmoles) wasadded dropwise and the reaction mixture was allowed to stir at roomtemperature for 30 min. The reaction mixture was poured in water (50 ml)and extracted with ethyl acetate (3×50 ml). The organic layer was washedwith water (3×50 ml) followed by brine (50 ml), dried over Na₂SO₄ andconcentrated to give 5.5 gm of the title product as browncrystalline-solid,

IR (Neat, cm⁻¹): 652, 753, 953, 1037, 1160, 1220, 1266, 1308, 1335,1357, 1404, 1428, 1452, 1591, 1693, 1723, and 2936.

¹H NMR (300 MHz, DMSO-d₆, δ): 1.451-1.496 (t, J=6.9 Hz, 3H),4.263-4.332(q, J=6.9 Hz 2H), 7.212-7.237 (d, J=7.5 Hz, 1H), 7.331-7.355 (t, J=7.8Hz, 1H, 7.417-7.471 (t, J=7.7 Hz, 1H), 7.502-7.557 (t, J=7.5 Hz, 1H),7.760-7.788 (d, J=7.9 Hz, 1H), 8.139-8.165 (d, J=7.8 Hz, 1H),8.503-8.530 (d, J=8.1 Hz, 1H),10.204 (s, 1H).

Intermediate 77: 4-bromo-1-ethoxy 9H-9-carbazole carbaldehyde

To a stirred solution of intermediate 76 (5.5 gm, 23 mmoles) in glacialacetic acid (30 ml) at 0° C., a solution of bromine (1.3 ml, 25.29mmoles) in glacial acetic acid (15 ml) was added dropwise and thereaction mixture was stirred at the same temperature for 30 min. Thereaction mixture was poured in water (60 ml), stirred for 10 min. andthe separated solid was filtered. The solid was washed with water (3×100ml) and dried to give 6.2 gm of the title product as brown crystallinesolid.

IR (Neat, cm⁻¹): 671, 772, 1020, 1096, 1219, 1246, 1316, 1384, 1594,2928, and 3368.

¹H NMR (300 MHz, DMSO-d₆, δ): 1.449-1.495 (t, J=6.9 Hz,3H),4.267-4.337(q,J=6.9Hz 2H), 7.193-7.222 (d, J=8.7 Hz, 1H), 7.495-7.654 (m, 3H),8.600-8.628 (d, J=8.4 Hz, 1H), 8.667-8.691 (d, J=7.2 Hz, 1H),10.244(s,1H).

Intermediate 78: 4-bromo-1-ethoxy 9H-carbazole

To a stirred solution of intermediate 77 (6.2 gm, 19.48 mmoles) inethanol (30 ml), aqueous 6M NaOH soln.(3.5 ml) was added and thereaction mixture was refluxed for 1 hour. Ethanol was evaporated fromthe reaction mixture under reduced pressure and extracted with ethylacetate (3×30 ml). The organic layer was washed with water (2×20 ml),dried over Na₂SO₄ and concentrated to give 1.7 gm of the title productas a thick liquid.

IR (KBr, cm⁻¹): 489, 566, 628, 663, 715, 731, 748, 792, 800, 1039, 1093,1108, 1207, 1229, 1254, 1286, 1326, 1387, 1409, 1451, 1474, 1487, 1571,2976, and 3378.

¹H NMR (300 MHz, DMSO-d₆, δ): 1.443-1.490 (t,J=6.9 Hz,3H),4.208-4.278(q,J=6.9 Hz 2H), 6.902-6.930 (d, J=8.4 Hz, 1H), 7.175-7.243 (m,2H),7.403-7.453 (t,J=7.3 Hz, 1H), 7.529-7.555 (d, J=7.8 Hz, 1H),8.494-8.522 (d, J=8.4 Hz,1H),11.554 (s,1H).

Intermediate 79: 1-ethoxy 9H-4-carbazole carbaldehyde

To a stirred solution of intermediate 78(1.5 gm, 5.169 mmoles) in sodiumdried ether (30 ml) at room temperature, 2.5 M n-BuLi (41.35 mmoles) wasadded dropwise and the reaction mixture was stirred at the sametemperature for 2 hours. The reaction mixture was cooled to 0° C. anddry DMF (3.20 ml 41.35 mmoles) was added and the reaction mixture wasstirred at room temperature for 2 hours. Ice pieces were added to thereaction mixture followed by 1N HCl (10 ml) and extracted with ethylacetate (3×15 ml). The organic layer was washed with brine (15 ml),dried over Na₂SO₄ and concentrated to give 0.9 gm of crude materialwhich was purified by column chromatography, to give 0.75 gm of thetitle compound as an off white solid.

IR (KBr, cm⁻¹): 505, 566, 578, 633, 667, 710, 740, 777, 788, 882, 944,1029, 1052, 1106, 1191, 1271, 1292, 1325, 1325, 1391, 1419, 1456, 1469,1552, 1609, 1623, 1658, 2870, 2931, 2957 and 3197.

¹H NMR (300 MHz, DMSO-d₆, δ): 1.500-1.547 (t,J=7.0 Hz,3H),4.374-4.442(q,J=6.9 Hz 2H), 7.143-7.230 (m, 2H), 7.409-7.464 (t,J=7.7 Hz, 1H),7.557-7.585 (d, J=8.4 Hz, 1H), 7.799-7.825 (d, J=7.8 Hz, 1H),8.993-9.021(d, J=8.4 Hz, 1H),10.144 (s,1H),11.713 (s, 1H).

Intermediate 80: Methyl-1-ethoxy-9H-4-carbazolecarboxylate derivatives

To a solution of intermediate 79 (0.75 gm, 3.318 mmoles) in a 2:1mixture of acetone and water (15 ml) at 0° C., sulphamic acid (0.61 gm,6.276 mmoles) was added followed by a solution of sodium chlorite (0.43gm, 4.707 mmoles) in water (5 ml) and the reaction mixture was stirredat room temperature for 2 hours. Acetone was evaporated from thereaction mixture under reduced pressureor and extracted with ethylacetate (2×25 ml).The organic layer was washed with brine (25 ml), driedover Na₂SO₄ and concentrated to give 0.81 gm of material containingmixture of expected compound and its 6-chloro substituted isomer. To asolution of above mixture (0.8 gm) in dry chloroform (15 ml) thionylchloride (0.69 ml,) was introduced followed by two drops of dry DMF at25° C. under anhydrous conditions. After complete conversion of acid toacid chloride, methanol (15 ml) was added to the reaction mixture at 25°C., under nitrogen atmosphere, the reaction mixture was stirred for 15min. The reaction mixture was adsorbed on silica gel and purified bycolumn chromatography to yield methyl-1-ethoxy-9H-1carbazolecarboxylate(475 mg) as a brown solid andmethyl-6-chloro-I-ethoxy-9H-4-carbazolecarboxylate (91 mg) as a brownsolid.

Intermediate 80a: Methyl-1-ethoxy-9H-4-carbazolecarboxylate

IR (KBr, cm⁻¹): 491, 524, 595, 637, 743, 758, 779, 953, 1043, 1095,1127, 1141, 1202, 1228, 1260, 1281, 1308, 1359, 1389, 1406, 1438, 1485,1513, 1566, 1608, 1621, 1677, 2971 and 3403.

¹H NMR (300 MHz, DMSO-d₆, δ): 1.479-1.524 (t, J=6.9 Hz, 3H),3.930(s,3H), 4.309-4.377 (q, J=6.9 Hz,2H),7.042-7.071 (d, J=8.7Hz,1H),7.107-7.157 (t, J=7.5 Hz, 1H), 7.375-7.425 (t, J=7.5 Hz,1H),7.533-7.559 (d, J=7.8 Hz, 1H),7.778-7.807(d, J=8.7 Hz,1H),8.763-8.790 (d, J=8.1 Hz, 1H),11.564 (s, 1H).

Intermediate 80b: Methyl-6-chloro-1-ethoxy-9H-4-carbazolecarboxylate

IR (KBr, cm⁻¹): 466, 569, 638, 725, 745, 774, 801, 886, 917, 970, 1026,1043, 1065, 1104, 1120, 1135, 1184, 1197, 1223, 1259, 1309, 1361, 1390,1429, 1444, 1459, 1569, 1612, 1725, 2930, 2973, and 3418.

¹H NMR (300 MHz, DMSO-d₆, δ): 1.475-1.522 (t, J=6.9Hz, 3H), 3.932(s,3H),4.317-4.387 (q, J=6.9 Hz,2H), 7.089-7.117(d, J=8.4 Hz,1H),7.417-7.453 (dd,J=8.6 Hz, 1H), 7.544-7.573 (d,J=8.7 Hz, 1H), 7.836-7.864(d, J=8.4 Hz,1H), 8.891-8.897 (d, J=1.8 Hz, 1H), 11.781 (s, 1H).

Intermediate 81:Methyl-6-chloro-9-(4-fluorobenzyl)-1-methoxy-9H-4-carbazole carboxylate

To a solution of intermediate 73b (500 mg 1.727mmoles) in dry DMF (10ml), under N₂ atmosphere, 60% sodium hydride (113.05 mg, 2.591 mmoles)was added at 0° C. and the reaction mixture was stirred at 0° C. for 15min and at 25 ° C. for 30 min. then 4-fluorobenzyl bromide (0.22ml,1.727 mmoles) was added to the reaction mixture at 0 ° C., stirredfor 15 min at 0° C. and then at 25° C. for 1 hr. The reaction mixturewas poured into ice-cold water and acidified with 1N HCl. The compoundwas extracted with ethyl acetate (2×10 ml), combined the organic layersand washed with water (10 ml) and with brine (10 ml). The organic layerwas dried over anhydrous sodium sulphate and concentrated to yield 396mg of the title compound as creamish solid.

¹HNMR(300 MHz,DMSO-d₆,δ): 3.943 (s, 3H), 3.968 (s, 3H), 5.932 (s, 2H),7.045-7.078 (m, 4H),7.1567.183 (d, J=8.1 Hz,1H),7.481-7.516 (dd, J=8.7Hz,1H), 7.705-7.734 (d, J=8.7 Hz,1H), 7.853-7.880 (d, J=8.1 Hz,1H),8.902-8.910 (d, J=2.4 Hz,1H),

Intermediate 82: 6-Chloro-9-(4-fluorobenzyl)-1-methoxy-9H-4-carbazolecarboxylic acid

To a solution of intermediate 81 (394 mg 0.991mmoles) in 5 mL methanol,5 mL of 50% sodium hydroxide solution was added and refluxed overnight.Methanol from the reaction mixture was evaporated under reducedpressure, and aqueous layer was acidified with 1N HCl and filtered toyield 324 mg of title compound as off-white solid.

¹HNMR(300 MHz,DMSO-d₆, δ): 3.961 (s, 3H), 5.931 (s, 2H), 7.049-7.078 (m,4H),7.135-7.163 (d, J=8.4 Hz,1H),7.469-7.498 (dd, J=8.7 Hz,1H),7.687-7.716 (d, J=8.7 Hz, 1H), 7.846-7.874 (d, J=8.4 Hz,1H), 8.992-8.998(4, J=1.8 Hz)1H),

Intermediate 83: 4-Hydroxydibenzothiophene

n-Butyllithium (26.25 g, 406 mmols, 175 ml of 2.4 M solution in hexane)was added to a stirred solution of dibenzothiophene (25 g, 135.7 mole)in dry THF (200 ml) at 0° C. over a period of 1 hr under dry N₂atmosphere. This reaction mixture was stirred overnight at roomtemperature and dry oxygen gas was bubbled into the reaction mixtureover 5 hrs. This reaction mixture was poured slowly over cold 1N HCl(500 ml). The organic layer was separated and the aqueous layer wasextracted with ethyl acetate (3×500 ml). Organic layers were mixedtogether and concentrated to dryness to get crude product (32 g). Thecrude product was purified by silica gel column chromatography.

Yield: 9 g (33%). As light brown colour solid.

¹H-NMR. (CDCl₃, 300 MHz, TMS, δ): 5.30 (s, 1H), 6.90 (d, 1H), 7.40 (t,1H), 7.50 (m, 2H), 7.80 (d, 1H), 7.85 (m, 1H) and 8.22 (m, 1H).

Intermediate 84: 4-methoxydibenzothiophene

To a solution of intermediate 83 (1.2 g, 6 mmols) in dry acetone (10 ml)was added K₂CO₃ (1.65 g, 12 mmols) followed by dimethyl sulphate (1.5 g,12 mmols) and the reaction mixture was refluxed for 6 h and stirredovernight at room temperature to complete the reaction. The reactionmixture was diluted with water and extracted with ethyl acetate. Ethylacetate layer was washed with water, brine, dried over sodium sulphateand concentrated to get the crude product which was purified by silicagel column chromatography as light yellow colored solid.

Yield: 0.88 g (68.75%).

¹H-NMR: (CDCl₃, 300 MHz, TMS, δ): 4.03 (s, 3H), 6.92 (d, 1H), 7.24-7.45(mixed, 3H), 7.78 (d, 1H) 7.87 (m, 1H), 8.12 (m, 1H).

Intermediate 85: 1-bromo4-methoxydibenzothiophene

To a solution of intermediate 84 (0.88 g, 4.1 mmols) in glacial aceticacid (40 ml) was added dropwise a solution of bromine (0.66 g, 4.1mmols) in acetic acid (10 ml) at room temperature. After 1 hr reactionmixture was poured into ice cold water. The precipitated product wasfiltered and dried. Crude product was purified by silica gel columnchromatography to get a white solid

Yield: 0.88 g (73%),mp.: 108-110° C.

¹HNMR: (CDCl₃, 300 MHz, TMS, δ): 4.02 (s, 3H), 6.77 (d, 1H), 7.50 (m,2H), 7.55 (d, 1H), 7.88 (m, 1H), 9.17 (m, 1H).

Intermediate 86: 4-methoxydibenzothiophene-1-carboxylic acid

n-Butyllithuim (3.4 mmoles, 1.45 ml of 2.4M solution in hexane) wasadded to a solution of intermediate 85(0.8 g, 2.7mmols) in driedether(30 ml) at 0° C. under N₂ atmosphere. After 20 minutes dry CO₂ wasbubbled into the reaction mixture at the same temperature for 1 hrperiod. The reaction mixture was poured in ice cooled 1 N HCl (100 ml)and extracted with ethyl acetate. The ethyl acetate layer was washedwith 5% NaHCO₃ solution (50 ml). The NaHCO₃ layer was then acidifiedwith 1N HCl, white precipitate thus obtained was washed with water anddried to get the pure product

Yield: 0.41 g (60%),m.p.: 248-249° C.

¹H-NMR: (CDCl₃, 300 MHz, TMS, δ): 4.11 (s, 3H), 6.94 (d, 1H), 7.25-750(m, 2H), 7.90 (dd, 1H), 8.15 (d, 1H), 8.92 (dd, 1H).

Intermediate 87: Methyl 4-methoxydibenzothiophene-1-carboxylate

To a solution of intermediate 86 (1.5 g, 5.8 mmols) in dry benzene (25ml) was added a drop of dry DMF and oxalylchloride (0.75 ml, 8.7 mmols)under N₂ atmosphere. This reaction mixture was stirred overnight at roomtemperature. To the reaction mixture dry methanol (5 ml) was added andreaction mixture refluxed for 0.5 h. The reaction mixture wasconcentrated to dryness to get crude product which was purified bysilica gel column chromatography using ethyl acetate and petroleum ethergradient

Yield: 1.42 gm

1H-NMR: (CDCl₃, 300 MHz, TMS, δ): 4.075 (s, 3H), 4.04 (s, 3H), 6.9 (d,1H), 7.2-75 (m, 2H), 7.90 (d, 2H), 8.6 (d, 1H).

Intermediate 88: 4-cyclopentyloxydibenzothiophene

To a solution of intermediate 83 (2 g, 9.98 mmols ) in dry DMF (10 ml)potassium carbonate (2.8 g, 20 mmols) and cyclopentyl bromide (3.72 g,25 mmols) was added under nitrogen atmosphere. This reaction mixture washeated at 80° C. for 5 h to complete the reaction. The reaction mixturewas quenched with water and extracted with ethyl acetate to get thecrude product which was purified by silica gel column chromatography assticky solid.

Yield: 1.45 g (54 %)

¹H-NMR: (CDCl₃, 300 MHz TMS, δ): 1.62-1.70 (m, 2H), 1.80-2.10 (m, 6H),5.00 (m, 1H), 6.90 (d, 1H), 7.30-7.45 (mixed, 3H), 7.72 (d, 1H), 7.85(m, 1H) and 8.11 (m, 1H).

Intermediate 89: 1-bromo-4-cyclopentyloxydibenzothiophene

To a solution of intermediate 88 (1.4 g, 5.21 mmols) in glacial aceticacid (40 ml) was added dropwise a solution of bromine (0.26 ml, 5.21mmols) in acetic acid (20 ml) at room temperature. After 1 hr reactionmixture was poured into ice cold water. The precipitated product wasfiltered and dried. Crude product was purified by silica gel columnchromatography to get a white solid

Yield: 1.7 g (77%), white solid, m.p.: 110-112° C.

¹H-NMR: (CDCl₃, 300 MHz, TMS, δ): 1.65-1.70 (m, 2H), 1.82-2.00 (m, 6H),4.96 (m, 1H), 6.77 (d, 1H), 7.45-7.50 (m, 2H), 7.54 (d, 1H), 7.85 (m,1H) and 9.15 (m, 1H).

Intermediate 90: 4-cyclopentyloxydibenzothiophene-1-carboxylic acid

n-Butyllithuim (3.4 mmoles, 1.45 ml of 2.4M solution in hexane) wasadded to a solution of intermediate 89 (1 g, 2.87 mmols) in dry ether(30ml) at 0° C. under N₂ atmosphere. After 20 minutes dry CO₂ was bubbledinto the reaction mixture at the same temperature for 1 hr period. Thereaction mixture was poured in ice cooled 1 N HCl (100 ml) and extractedwith ethyl acetate. The ethyl acetate layer was washed with 5% NaHCO₃solution (50 ml). The NaHCO₃ layer was then acidified with 1N HCl, whiteprecipitate thus obtained was washed with water and dried to get thepure product

Yield: 0.52 g, (58%), white solid, m.p.: 205-206° C.

¹H-NMR: (CDCl₃+1drop DMSO-d₆, 300 MHz, TMS, δ): 1.50-1.60 (m, 2H),1.69-1.80 (m, 6H), 4.88 (m, 1H), 6.72 (d, 1H), 7.19-7.3 (m, 2H),7.65-7.68 (dd, 1H), 7.76 (d, 1H), and 8.67 (m, 1H).

Intermediate 91: 4-ethoxy dibenzothiophene

Sodium hydride (50% dispersion,0.24 g,0.01 moles, 1 eq) was added to asolution of intermediate 83 (2 g, 0.01 moles, 1 eq) in 10 ml of (dry)DMF at 0° C. for 30-35 minutes and ethyl iodide (3.2 g, 0.02 moles) wasadded. The reaction mixture was stirred 2 hours at room temperature thenthe reaction quench with ethyl acetate and washed with water, brine. Theorganic layer on concentration gave a crude product which was purifiedby silica gel column chromatography.

Yield: 2 g,

IR (KBr, cm-1): 3685, 3400, 3067, 3019, 2986, 2932, 2400, 1906, 1601,1570, 1459, 1485, 1475, 1442, 1392, 1306, 1322, 1263, 1216, 1087, 1119,1052, 755 and 669.

¹H-NMR(CDCl₃, 300 MHz, TMS, δ): 1.52 (t, 3H), 4.25 (q, 2H), 6.88 (d,1H), 7.34-7.45 (mixed, 3H), 7.73 (d, 1H), 7.82-7.88 (m, 1H), 8.07-8.12(m, 1H)

Intermediate 92: 1-bromo-4-ethoxy dibenzothiophene

To a solution of intermediate 91 (1.7 g, 7.45 mmols) in glacial aceticacid (40 ml) was added dropwise a solution of bromine (0.38 ml, 7.45mmols) in acetic acid (10 ml) at room temperature. After 1 hr reactionmixture was poured into ice cold water. The precipitated product wasfiltered and dried. Crude product was purified by silica gel columnchromatography to get a yellow solid. Yield : 2 g,

IR (KBr, cm-1): 3330, 2970, 2882, 1557, 1471, 1433, 1394, 1360, 1309,1294, 1250, 628

¹H-NMR (CDCl₃, 300 MHz, TMS, δ): 1.53 (t, 3H), 4.25 (q, 2H), 6.75 (d,1H), 7.47-7.50 (m, 2H), 7.56 (d, 1H), 7.85-7.88 (m, 1H), 9.14-9.17 (m,1H)

Intermediate 93: 4-ethoxy dibenzo thiophene 1-carboxylic acid

n-Butyllithuim (6.5 mmols, 2.78 ml of 2.4 M in hexane) was added to asolution of intermediate 92 (1.98 g, 6.51 mmols) in dried ether(30 ml)at 0° C. under N₂ atmosphere. After 20 minute dry CO₂ was bubbled intothe reaction mixture at the same temperature for 1 hr period Thereaction mixture was poured in ice cooled 1 N HCl (100 ml) and extractedwith ethyl acetate. The ethyl acetate layer was washed with 5% NaHCO₃solution (50 ml). The NaHCO₃ layer was then acidified with 1N HCl, whiteprecipitate thus obtained was washed with water and dried to get thepure product.

Yield: 0.7 g, white solid

IR (KBr, cm-1): 3069, 2937, 2978, 2682, 1683, 1583, 1553, 1442, 1392,1295, 1238, 1271, 1163, 1129, 1116, 1066, 756, 703, 643, 518.

¹H-NMR (DMSO, 300 MHz, TMS, δ): 1.47 (t, 3H), 4.37 (q, 2H), 7.18 (d,1H), 7.46-7.58 (m, 2H), 7.87 (d, 1H), 8.07(d, 1H), 8.69 (d, 1H)

Intermediate 94: 4-benzyloxydibenzothiophene

sodium hydride (50% dispersion, 0.24 g, 0.01 moles, 1 eq) was added to asolution of intermediate 83 (2 g, 9.9 mmols) in 10 ml of (dry)DMF at 0°C. for 30-35 minutes and benzyl bromide (1.88 g, 9.9 mmols) was added.The reaction mixture was stirred 2 hours at room temperature then thereaction quenched with ethyl actate and washed with water, brine. Theorganic layer on concentration gave a crude product which was purifiedby silica gel column chromatography.

Yield: 2.6 g,

¹H-NMR(CDCl₃, 300 MHz, TMS, δ): 5.29 (s, 2H), 6.94 (d, 1H), 7.31-7.50(mixed, 8H), 7.75 (d, 1H), 7.85 (m, 1H) and 8.11 (m, 1H)

Intermediate 95: 1-bromo-4-benzyloxy dibenzothiophene

To a solution of intermediate 94 (2.6 g, 8.96 mmols) in glacial aceticacid (40 ml) was added dropwise a solution of bromine (0.46 ml, 8.96mmols) in acetic acid (10 ml) at room temperature. After 1 hr reactionmixture was poured into ice cold water. The precipitated product wasfiltered and dried. Crude product was purified by silica gel columnchromatography to get a white solid.

Yield: 2.6 g,

¹H-NMR (CDCl₃, 300 MHz, TMS, δ): 5.28 (s, 2H), 6.79 (d, 1H), 7.32-7.39(m, 3H), 7.45-7.52 (mixed, 5 H), 7.86 (m, 1H) and 9.15 (m, 1H)

Intermediate 96: 4-benzyloxydibenzo thiophene-1-carboxylic acid

n-Butyllithuim (5.4 mmols, 2.31 ml of 2.4 M in hexane) was added to asolution of intermediate 95 (2 g, 5.42 mmols) in dried ether(30 ml) at0° C. under N₂ atmosphere. After 20 minute dry CO₂ was bubbled into thereaction mixture at the same temperature for 1 hr period. The reactionmixture was poured in ice cooled 1 N HCl (100 ml) and extracted withethyl acetate. The ethyl acetate layer was washed with 5% NaHCO₃solution (50 ml). The NaHCO₃ layer was then acidified with 1N HCl, whiteprecipitate thus obtained was washed with water and dried to get thepure product

Yield 0.5g,

¹H-NMR (CDCl₃, 300 MHz, TMS, δ): 5.38 (s, 2H), 6.96 (d, 1H), 7.34-7.43(mixed, 7H), 7.88 (d, 1H), 8.07 (d, 1H) and 8.89 (d, 1H)

Intermediate 97: 4-Ethyldibenzothiophene

n-Butyllithium (108 mmols, 46 ml of 2.4 M solution in hexane) was addedto a stirred solution of dibenzothiophene (10 g, 54 mmole) in dried THF(150 ml) at 0° C. over a period of 1 hr under dry N₂ atmosphere. Thisreaction mixture was stirred 5 hrs at room temperature then the reactionmixture was cooled to −70° C. and a solution of ethyl iodide in dry THFwas added dropwise and stirred at room temperature for over night. Thisreaction mixture was poured slowly into a cold 1N HCl (200 ml). Organiclayer was separated and the aqueous layer was extracted with ethylacetate (3×500 ml). Organic layers mixed together and concentrated todryness to get crude product. The crude product was purified by silicagel column chromatography.

Yield: 9.72 g (84.81%) as off white solid.

¹H-NMR (DMSO, 300 MHz, TMS, δ): 1.34 (t, 3H), 2.87 (q, 2H), 7.37 (d,1H),7.44-7.52 (mixed, 3H), 8.02 (m, 1H), 8.19 (d, 1H) and 8.33 (m, 1H).

Intermediate 98: 6-Ethyl-4-Hydroxydibenzothiophene

n-Butyllithium (18.8 mmols, 8.04 ml of 2.4 M solution in hexane) wasadded to a stirred solution of intermediate 97 (2 g, 9.4 mmole) in driedTHF (30 ml) at 0° C. over the period of 30 minuted under dry N₂atmosphere. This reaction mixture was stirred overnight at roomtemperature and dry oxygen gas bubbled in the reaction mixture over 5hrs. This reaction mixture was poured slowly to the cold 1N HCl (50 ml).Organic layer was separated and the aqueous layer was extracted withethyl acetate (3×50 ml).

Organic layers mixed together and concentrated to dryness to get crudeproduct (32 g). The crude product was purified by silica gel columnchromatography.

Yield: 0.5 g (23%). As light yellow color solid.

¹H-NMR: (CDCl₃, 300 MHz, TMS, δ): 1.42 (t, 3H), 2,95 (q, 2H), 5.32 (s,1H), 6.86 (d, 1H), 7.29 (mixed, 2H), 7.41 (t, 1H), 7.75 (d, 1H), 7.97(d, 1H)

Intermediate 99: 6-Ethyl-4-methoxy-dibenzothiophene

Sodium hydride (50% dispersion, 0.06 g, 2.60 mmols) was added to asolution of intermediate 98 (0.5 g, 2.2 mmols) in 10 ml of (dry)DMF at0° C. for 30-35 minute and methyl iodide (0.62 g, 4.3 mmols) was added.The reaction mixture was stirred for 4 h at room temperature then thereaction quenched with ethyl acetate and washed with water, brine whichon concentration gave crude product which was purified by silica gelcolumn chromatography.

Yield. 0.5 g (97%), off white solid

¹H-NMR(CDCl₃, 300 MHz, TMS, δ): 1.41 (t, 3H), 2.95 (q, 2H), 4.03 (s,3H), 6.90 (d, 1H), 7.28 (d, 1H), 7.37-7.45 (m, 2H), 7.74 (d, 1H), 7.97(d, 1H),

Intermediate 100: 6-Ethyl-4-methoxy-dibenzothiophene-1-carbaldehyde

To a solution of intermediate 99 (0.15 g, 0.61 mmols) in drydichloromethane (10 ml) was added SnCl₄ (0.1 g, 0.418 mmols) followed bydropwise addition of a solution of dichloro(methoxy)methane (0.05 g,0.478 mmols) in dichlomethane (5 ml) at 0° C. After addition thereaction mixture was stirred at 0° C. for 1 hr. The reaction mixture wasdiluted with water and extracted with chloroform which on concentrationgave a crude product which was purified by silica gel columnchromatography.

Yield: 009 g (52%) white solid

¹H-NMR(CDCl₃, 300 Mz, TMS, δ): 1.43 (t, 3H), 2.98 (q, 2H), 4.13 (s, 3H),7.02 (d, 1H), 7.37 (d, 1H), 7.47 (t, 1H), 7.99 (d, 1H), 8.96 (d, 1H) and10.51 (s, 1H)

Intermediate 101: 6-Ethyl-4-methoxy-dibenzothiophene-1-carboxylic acid

To a mixture of the intermediate 100 (0.08g, 0.29 mmols ) inacetone-water (2:1, 50 ml) was added sulphamic acid (0.043 g, 0.44mmols) followed by addition of sodium chlorite (0.04 g, 0.44 mmols) in 4portions at 0° C. The reaction mixture was stirred at room temperaturefor 3 hrs. Acetone was evaporated and reaction mixture was extractedwith ethylacetate. Ethyl acetate layer on concentration gave crudeproduct which was purified by silica gel column chromatography.

Yield: 0.05 g (62%) white solid

¹H-NMR(CDCl₃, 300 MHz, TMS, δ): 1.43 (t, 3H), 2.97 (q, 2H), 4.11 (s,3H), 6.92(d, 1H), 7.33 (d, 1H), 7.42 (t, 1H), 8.11 (d, 1H) and 8.73 (d,1H).

Intermediate 102: Methyl 4-hydroxydibenzothiophene 1-carboxylate

Pieces of dry aluminium foil (0.039 g, 1.44 mmols) and Iodine (0.59 g,4.6 mmols) were refluxed in CS₂ till the disappearance of iodine colour.To this solution a solution of intermeadiate 87 (0.2 g, 0.7 mmols) inCS₂ was added dropwise at room temperature with stirring. After additionreaction mixture was refluxed for 1 hr then cooled reaction mixture waspoured on crushed ice and extracted with ethyl acetate. Ethyl acetatelayer on concentration gave crude product which was purified by silicagel column chromatography.

Yield: 0.17 g (93%), white solid.

¹H-NMR: (CDCl₃, 300 Mz, TMS, δ): 4.04 (s, 3H), 5.91 (br s, 1H), 6.84 (d,1H), 7.40-7.50 (p, 2H), 7.77 (d, 1H), 7.87 (d, 1H), and 8.59 (d, 1H)

Intermediate 103: Methyl 4-difluromethoxydibenzothiophene-1-carboxylate

To a solution of intermediate 102 (0.2 g, 4.16 mmols) in dry DMF, NaH(0.2 g 50% dispersion in oil, 4.16 mmols) was added at 0° C. and stirredfor 30 min. at 50° C. To this reaction mixture CHF₂Cl gas was passed for2 hrs at room temperature. The reaction mixture was diluted with waterand extracted with ethyl acetate. Ethyl acetate layer on concentrationgave crude product which was purified on silica gel columnchromatography.

Yield: 0.15g (70% )

¹H-NMR. (CDCl₃, 300 MHz, TMS, δ): 4.06 (s, 3H), 6.73 (t, J=72.6 Hz, 1H),7.21 (d, 1H), 7.44-7.50 (m, 2H), 7.78 (d, 1H), 7.87 (d, 1H) and 8.47 (d,1H)

Intermediate 104: 4-Difluromethoxydibenzothiophene-1-carboxylic acid

The intermediate 103 (0.14 g, 0.5 mmols) was hydrolysed with KOH (0.05g, 0.99 mmols) in MeOH (5 ml) and water (5 ml) at 50° C. for 2 hrs. MeOHwas removed and the reaction mixture was acidified with 1N HCl andextracted with ethyl acetate. Ethyl acetate layer on concentration gavepure product.

Yield. 0.12 g (87%), M.P.: 196-198° C.

¹H-NMR: (CDCl₃, 300 MHz, TMS, δ): 6.77 (t, J=72 Hz, 1H), 7.26 (d, 1H),7.45-7.50 (m, 2H), 7.90 (d, 1H), 8.06 (d, 1H) and 8.79 (d, 1H)

The following examples are representative compounds of the invention butshould not be construed as limiting in any way.

EXAMPLE 1 N-(3,5-dichloropyrid-4-yl)-4-methoxydibenzo[b,d]furan-1-carboxamide

A suspension of intermediate 4 (100 mg, 0.00413 mol) in a mixture ofbenzene (2 ml) and freshly distilled thionyl chloride (2 ml) was heatedto reflux temperature for 4 h. The excess thionyl chloride was removedunder vacuum to get the corresponding acid chloride.

To a pre-washed suspension of sodium hydride (9.0 mg, 1.5 equiv., 0.61mmol, 60% oil dispersion) in DMF (2 ml) was added dropwise a solution of4-amino-3,5-dichloropyridine (68 mg, 0.41 mmol) in DMF (2 ml) at −10° C.A pre-cooled solution of above acid chloride in THF (2 ml) was added,all at once, to the reaction mixture and the contents were stirred at−10° C. for 30 min. The reaction was quenched with brine, diluted withwater and extracted with ethyl acetate. The organic layer was washedwith water, 5% HCl, 5% sodium bicarbonate and brine solution.Evaporation of solvent and washing of the resulting crude solid withmethanol provided N-(3,5-dichloropyrid-4-yl)-4-methoxydibenzo[b,d]furan-1-carboxamide as a white solid (15 mg); mp: 302° C.

IR (KBr) 3171, 2974, 1654, 1607, 1491, 1450, 1293, 1202, 1098, 1011, 756cm ⁻¹.

¹H NMR (300 MHz, DMSO) δ 4.07 (s, 3H), 7.32 (d, 1H, J=8.4 Hz), 7.34 (t,1H, J=8.4 Hz), 7.52 (t, 1H, J=8.1 Hz), 7.74 (d, 1H, J=8.1 Hz), 7.89 (d,1H, J=8.4 Hz), 8.41 (d, 1H, J=8.1 Hz), 8.77 (s, 2H), 10.8 (s, 1H).

EXAMPLE 2 N-(3,5-dichloropyrid-4-yl)-4-methoxydibenzo[b,d]furan-1-carboxamide-N1-oxide

A suspension of N-(3,5-dichloropyrid-4-yl)-4-methoxydibenzo[b,d]furan-1-carboxamide (200 mg, 0.518 mmol) (example 1) andm-chloroperbenzoic acid (50-55%) (880 mg, 2.5 mmol) in chloroform (10ml) was refluxed for 2 h. The reaction was cooled and washed withsaturated sodium bicarbonate and water. The organic solvent wasdistilled of in vacuo and the residue was purified by columnchromatography using 20% acetone-chloroform as the eluent to give 150 mgof N-(3,5-dichloropyrid-4-yl)-4-methoxydibenzo[b,d]furan-1-carboxamide-N1-oxide as white solid; mp: 265-270° C.

IR (KBr) 3214, 3060, 3007, 2931, 1655, 1474, 1454, 1282, 1245, 1099,1011, 751 cm ⁻¹.

¹H NMR (300 MHz, DMSO) δ 4.07 (s, 3H), 7.33 (d, 1H, J=8.4 Hz), 7.35 (t,1H, J=8.4 Hz), 7.55 (t, 1H, J=8.1 Hz), 7.74 (d, 1H, J=8.1 Hz), 7.88 (d,1H, J=8.4 Hz), 8.41 (d, 1H, J=8.1 Hz), 8.76 (s, 2H), 10.64 (s, 1H).

EXAMPLE 3 N-(pyrid-4-yl)-4-methoxy dibenzo[b,d]furan-1-carboxamide

A suspension of intermediate 4 (100 mg, 0.00413 mol) in a mixture ofbenzene (2 ml) and freshly distilled thionyl chloride (2 ml) was heatedto reflux temperature for 4 h. The excess thionyl chloride was removedunder vacuum to get the corresponding acid chloride.

A solution of above acid chloride (0.249 mmol) in dry THF (5 ml) wasadded to a solution of 4-aminopyridine (22 mg, 0.249 mmol) anddiisopropylethylamine (50 mg, 0.49 mmol) in dry THF (5 ml) at roomtemperature. The reaction mixture was stirred at room temperature for 16h. The reaction mixture was diluted with water (25 ml) and extractedwith ethyl acetate (15 ml×3). The ethyl acetate extract was concentratedin vacuo and the residue was purified by silica gel chromatography using15% acetone-chloroform as the eluent to obtain 20 mg ofN-(pyrid4-yl)-4-methoxy dibenzo[b,d]furan-1-carboxamide as a whitesolid; mp: 215° C.

IR (KBr) 3294, 2923, 2852, 1657, 1585, 1411, 1281, 1096, 814 cm ⁻¹.

¹H NMR (300 MHz, CDCl₃) δ 4.15 (s, 3 H), 7.04 (d, 1H, J=8.4 Hz), 7.39(t, 1H, J=8.4 Hz), 7.53 (t, 1H, J=8.4 Hz), 7.65 (m, 4H), 7.93 (brs, 1H),8.36 (d, 1H, J=7.2 Hz), 8.61 (brs, 2H).

EXAMPLE 4 N(pyrid-4-yl)-4-methoxydibenzo[b,d]furan-1-carboxamide-N1-oxide

A suspension of N-(pyrid-4-yl)-4-methoxy dibenzo[b,d]furan-1-carboxamide(150 mg, 0.47 mmol) (example 3) and m-chloroperbenzoic acid (50-55%)(406 mg, 2.3 mmol) in chloroform (2.5 ml) was stirred at roomtemperature for 16 h. Chloroform was evaporated and the resulting solidwas washed with saturated sodium bicarbonate solution, water, dried andthen purified by column chromatography using 20% acetone-chloroform asthe eluent to give 70 mg of N-pyrid-4-yl)-4-methoxydibenzo[b,d]furan-1-carboxamide-N1-oxide as white solid; nip: 246-251°C.; IR (KBr): 3207, 3116, 3056, 2931, 2840, 2797, 1678, 1626, 1603,1530, 1485, 1458, 1439, 1391, 1330, 1277, 1214, 1174, 1122, 1099, 1023,851, 829, 791, 749 cm ⁻¹.

¹H NMR (300 MHz, DMSO) δ 4.07 (s, 3H), 7.32 (d, 1H, J=8.4 Hz), 7.34 (t,1H, J=8.4 Hz), 7.56 (t, 1H, J=8.4 Hz), 7.65 (m, 2H), 7.84 (d, 2H, J=7.2Hz), 8.18 (d, 2H, J=7.2 Hz), 8.30 (d, 1H, J=8.4 Hz), 10.96 (s, 1H).

EXAMPLE 5 N-(2-chloropyrid-3-yl)-4-methoxydibenzo[b,d]furan-1-carboxamide

A suspension of intermediate 4 (100 mg, 0.00413 mol) in a mixture ofbenzene (2 ml) and freshly distilled thionyl chloride (2 ml) was heatedto reflux temperature for 4 h. The excess thionyl chloride was removedunder vacuum to get the corresponding acid chloride.

To a pre-washed suspension of sodium hydride (41 mg, 2.5 equiv., 1.0mol, 60% oil dispersion) in DMF (4 ml) was added dropwise a solution of2-chloro-3-aminopyridine (79 mg, 0.61 mmol) in DMF (4 ml) at −10° C. Apre-cooled solution of above acid chloride in THF (2 ml) was added, allat once, to the reaction mixture and the contents were stirred at −10°C. for 30 min. The reaction was quenched with brine, diluted with waterand extracted with ethyl acetate. The organic layer was washed withwater, 5% HCl, 5% sodium bicarbonate and brine solution. Evaporation ofsolvent gave a crude solid which was purified by column chromatographyusing 5% acetone-chloroform as eluent to giveN-(2-chloropyrid-3-yl)-4-methoxy dibenzo[b,d]furan-1-carboxamide as awhite solid (30 mg); mp: 192° C.

IR (KBr): 3254, 2924, 1651, 1579, 1525, 1505, 1451, 1389, 1297, 1283,1202, 1098, 1010, 748 cm⁻¹

¹H NMR: (300 MHz, DMSO) δ 4.07 (s, 3H), 7.34 (m, 2H), 7.54 (m, 2H), 7.88(d, 1H, J=8.4 Hz), 7.86 (d, 1H, J=7.86 Hz), 8.20 (d, 1H, J=7.8 Hz),8.32(d, 1H, J=4.8 Hz), 10.36 (s, 1H).

EXAMPLE 6 N-(4-fluorophenyl)-4-methoxy dibenzo[b,d]furan-1carboxamide

A suspension of intermediate 4 (100 mg, 0.00413 mol) in a mixture ofbenzene (2 ml) and freshly distilled thionyl chloride (2 ml) was heatedto reflux temperature for 4 h. The excess thionyl chloride was removedunder vacuum to get the corresponding acid chloride.

To a solution of 4-fluoroaniline (45 mg, 0.406 mmol) anddiisopropylethylamine (79 mg, 0.6 mol) in dry THF (5 ml) at roomtemperature was added above solution of acid chloride (0.406 mmol) indry THF (5 ml). The reaction mixture was stirred at room temperature for10-12 h. The reaction mixture was diluted with 5% aqueous hydrochloricacid (10 ml) to precipitate the product The product washed withsaturated sodium bicarbonate solution followed by water and petroleumether. The solid was dried and purified by silica gel chromatographyusing petroleum ether: ethyl acetate (8:2) as the eluent to obtain 10 mgof N-(4-fluorophenyl)-4-methoxy dibenzo[b,d]furan-1-carboxamide as awhite solid; mp: 246° C.

IR (KBr) 3304, 2923, 1646, 1604, 1509, 1406, 1296, 1278, 1096, 823, 831cm ⁻¹.

¹H NMR (300 MHz, CDCl₃) δ 4.11 (s, 3H), 6.99 (d, 1H, J=8.4 Hz), 7.11 (t,2H, J=8.7 Hz), 7.32 (t, 1H, J=7.8 Hz), 7.5 (t, 1H, J=7.8 Hz), 7.60 (d,1H, J=8.4 Hz), 7.64 (d, 2H, J=7.2 Hz), 7.65 (d, 1H, J=7.8 Hz), 7.81 (s,1H), 8.35 (d, 1H, J=7.8 Hz).

EXAMPLE 7 N-(pyrid-3-yl)-4-methoxy dibenzo[b,d]furan-1-carboxamide

A suspension of intermediate 4 (100 mg, 0.00413 mol) in a mixture ofbenzene (2 ml) and freshly distilled thionyl chloride (2 ml) was heatedto reflux temperature for 4 h The excess thionyl chloride was removedunder vacuum to get the corresponding acid chloride.

A solution of acid chloride (0.61 mmol) in dry THF (5 ml) was added to asolution of 3-aminopyridine (57 mg, 0.61 mmol) and diisopropylethylamine(157 mg, 1.32 mmol) in dry THF (5 ml) at room temperature. The reactionmixture was stirred at room temperature for 16 h. The reaction mixturewas diluted with water (25 ml) and extracted with ethyl acetate (15ml×3). The ethyl acetate extract was concentrated in vacuo and theresidue was purified by silica gel chromatography using 15%acetone-chloroform as the eluent to obtain 60 mg ofN-(pyrid-3-yl)-4-methoxy dibenzo[b,d]furan-1-carboxamide as a whitesolid; mp: 226° C.

IR (KBr): 3272, 2936, 1646, 1582, 1520, 1484, 1409, 1340, 1286, 1204,1180, 1117, 1069, 826, 703 cm⁻¹.

¹H NMR: (300 MHz, DMSO): δ 4.20 (s, 3H), 7.45 (d, 2H, J=8.1 Hz), 7.99(t, 2H, J=7.2 Hz), 8.27 (d, 1H, J=8.1 Hz), 8.35 (s, 1H), 8.44 (d, 1H,J=6.9), 8.95 (brs, 1H), 9.37 (s, 1H), 10.76 (s, 1H).

EXAMPLE 8 N-(pyrid-3-yl)-4-methoxydibenzo[b,d]furan-1-carboxamide-N1-oxide

A suspension of N-(pyrid-3-yl)-4-methoxy dibenzo[b,d]furan-1-carboxamide(50 mg, 0.15 mmol) (example 8) and m-chloroperbenzoic acid (50-55%) (135mg, 0.78 mmol) in chloroform (10 ml) was stirred at room temperature for16 h Chloroform was evaporated and the resulting solid was washed withsaturated sodium bicarbonate solution, water, dried and then purified bycolumn chromatography using 20% acetone-chloroform as the eluent to give15 mg of N-(pyrid-3-yl)-4-methoxydibenzo[b,d]furan-1-carboxamide-N1-oxide as white solid; mp: 239-241° C.

IR (KBr): 2931, 2840, 2797, 2389, 1678, 1626, 1603, 1530, 1511, 1485,1439, 1395, 1313, 1277, 1294, 1214, 1203, 1174, 1099, 1122, 1036, 851,749 cm⁻¹.

¹H NMR: (300 MHz, DMSO): δ 4.06 (s, 3H), 7.29-7.39 (m, 3H), 7.56 (t, 1H,J=7.5 Hz), 7.85 (d, 2H, J=7.5 Hz), 7.94 (t, 1H, J=8.1 Hz), 8.18 (d, 2H,J=7.5 Hz), 8.31 (d, 1H, J=8.4 Hz), 10.96 (s, 1H).

EXAMPLE 9 N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-trifluoromethyldibenzo[b,d]furan-1-carboxamide

A suspension of intermediate 8 (100 mg, 0.00413 mol) in a mixture ofbenzene (2 ml) and freshly distilled thionyl chloride (2 ml) was heatedto reflux temperature for 4 h The excess thionyl chloride was removedunder vacuum to get the corresponding acid chloride.

To a pre-washed suspension of sodium hydride (27.0 mg, 2.0 equiv., 1.16mmol, 60% oil dispersion) in DMF (2 ml) was added dropwise a solution of4-amino-3,5-dichloropyridine (94 mg, 0.58 mmol) in DMF (2 ml) at −10° C.A pre-cooled solution of above acid chloride (0.58 mmol) in THF (2 ml)was added, all at once, to the reaction mixture and the contents werestirred at −10° C. for 30 min. The reaction was quenched with brine,diluted with water and extracted with ethyl acetate. The organic layerwas washed with water, 5% HCl, 5% sodium bicarbonate and brine solution.After removal of the organic solvent under vacuo the solid was purifiedby silica gel chromatography using 12% ethyl acetate: chloroform as theeluent to obtain N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-trifluromethyldibenzo[b,d]furan-1-carboxamide as a white solid (80 mg); mp: 298° C.

IR (KBr): 3203, 2936, 2848, 1669, 1554, 1489, 1392, 1327, 1286, 1217,1166, 1117, 1105, 809 cm⁻¹.

¹H NMR (300 MHz, DMSO) δ 4.11 (s, 3H), 7.44 (d, 1H, J=8.7 Hz), 7.91 (d,1H, J=8.7 Hz), 8.0 (d, 1H, J=8.7 Hz), 8.8 (s, 2H), 8.87 (s, 1H), 10.94(s, 1H).

EXAMPLE 10 N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-trifluoromethyldibenzo[b,d]furan-1-carboxamide-N1-oxide

A suspension ofN-3,5-dichloropyrid-4-yl)-4-methoxy-8-trifluoromethoxy-dibenzo[b,d]furan-1-carboxamide(70 mg, 0.175 mmol) (example 10) and m-chloroperbenzoic acid (50-55%)(121 mg, 0.703 mmol) in chloroform (5 ml) was stirred at roomtemperature for 16 h. Chloroform was evaporated and the resulting solidwas washed with saturated sodium bicarbonate solution, water, dried andthen purified by column chromatography using 25% acetone-chloroform asthe eluent to give 18 mg ofN-(3,5-dichloropyrid-4-yl)-4-methoxy-8-trifluoromethyl-dibenzo[b,d]furan-1-carboxamide-N1-oxideas white solid; mp: 272° C.

IR (KBr) 3184, 3067, 2934, 1658, 1537, 1479, 1429, 1326, 1284, 1241,1165, 1107, 896 cm ⁻¹.

¹H NMR (300 MHz, DMSO) δ 4.10 (s, 3 H), 7.43 (d, 1 H, J=8.7 Hz),7.91-8.02 (brm, 3H) 8.77 (s, 2H), 8.87 (s, 1H), 10.74 (s, 1H).

EXAMPLE 11 N(pyrid-4-yl)-4-methoxy-8-trifluoromethyldibenzo[b,d]furan-1-carboxamide

A suspension of intermediate 8 (100 mg, 0.00413 mol) in a mixture ofbenzene (2 ml) and freshly distilled thionyl chloride (2 ml) was heatedto reflux temperature for 4 h. The excess thionyl chloride was removedunder vacuum to get the corresponding acid chloride.

To a solution of 4-aminopyridine (52 mg, 0.645 mmol) anddiisopropylethylamine (0.3 ml) in dry THF (3 ml) was added a solution ofacid chloride (0.645 mmol) in dry THF (3 ml). The reaction mixture wasstirred at room temperature for 1 h. The reaction mixture was dilutedwith water (10 ml) and extracted with ethyl acetate (10 ml×3). The ethylacetate extract was concentrated under reduced pressure and the residuewas purified by silica gel chromatography using 20% acetone-chloroformas the eluent to obtain 60 mg ofN-(pyrid-4-yl)-4-methoxy-8-trifluoromethyldibenzo[b,d]furan-1-carboxamide as a white solid; mp: 259° C.

IR (KBr) 3308, 2936, 2848, 1660, 1587, 1494, 1411, 1324, 1283, 1207,1156, 1120, 1104, 818 cm ⁻¹.

¹H NMR (300 MHz, DMSO) δ 4.10 (s, 3H), 7.42 (d, 1H, J=8.4 Hz), 7.81 (d,2H, J=6.2 Hz), 7.93 (d, 2H, J=8.4 Hz), 8.01 (d, 1H, J=8.4 Hz), 8.51 (d,2H, J=5.4 Hz), 8.7 (s, 1H), 10.90 (s, 1H).

EXAMPLE 12N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-trifluoromethyldibenzo[b,d]furan-1-carboxamide

A suspension of intermediate 12 (100 mg, 0.00413 mol) in a mixture ofbenzene (2 ml) and freshly distilled thionyl chloride (2 ml) was heatedto reflux temperature for 4 h. The excess thionyl chloride was removedunder vacuum to get the corresponding acid chloride.

A solution of 4-amino-3,5-dichloropyridine (75 mg, 0.46 mmol) in DMF(2.5 ml) was added dropwise to a pre-washed suspension of sodium hydride(44 mg, 2.0 equiv., 0.92 mmol, 60% oil dispersion) in DMF (2.5 ml) at−10° C. A pre-cooled solution of above acid chloride (0.462 mmol) in THF(2 m1l) was added, all at once, to the reaction mixture and the contentswere stirred at −10° C. for 30 min. The reaction was quenched withbrine, diluted with water and extracted with ethyl acetate. The organicextract was washed with water, 5% hydrochloric acid, 5% sodiumbicarbonate and brine solution. The organic solvent was distilled off invacuo and the residue was purified by silica-gel chromatography using12% ethyl acetate-chloroform as eluent to obtainN-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-trifluoromethyldibenzo[b,d]furan-1-carboxamide as a white solid ( 30 mg); mp: 228° C.

IR (KBr) 3200, 2930, 1664, 1555, 1492, 1389, 1325, 1286, 1272, 1168,1141, 1117, 827 cm⁻¹.

¹H NMR (300 MHz, DMSO) δ 7.60 (t, 1H, J=72.6 Hz) 7.68 (d, 1H, J=8.4 Hz),7.98 (d, 2H, J=8.4 Hz), 8.09 (d, 1H, J=8.4 Hz), 8.8 0(s, 1H), 8.82 (s,2H), 11.16 (s, 1H).

EXAMPLE 13 N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-trifluoromethyldibenzo[b,d]furan-1-carboxamide-N1-oxide

A suspension ofN-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-trifluoromethoxy-dibenzo-[b,d]-furan-1-carboxamide(120 mg, 0.244 mmol) (example 13) and m-chloroperbenzoic acid (50-55%)(168 mg, 0.477 mmol) in chloroform (5 ml) was stirred at roomtemperature 36 h. Chloroform was evaporated and the resulting solid waswashed with saturated sodium bicarbonate solution, water, dried andpurified by column chromatography using 20% acetone-chloroform as theeluent to give 40 mg ofN-3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-trifluoromethyl-dibenzo[b,d]furan-1-carboxamide-N1oxideas white solid; mp: 249.5° C.

IR (KBr) 3221, 3067, 2927, 2324, 1662, 1539, 1483, 1453, 1359, 1326,1284, 1240, 1116, 1101, 1056, 1033, 896 cm ⁻¹.

¹H NMR (300 MHz, DMSO) δ 7.60 (t, 1 H, J=72 Hz), 7.65 (d, 1H, J=8.4 Hz),7.99-8.09 (brm, 3H), 8.73 (s, 2H), 8.88 (s, 1H) 11.08 (s, 1H).

EXAMPLE 14 N-(pyrid-4-yl)-4-difluoromethoxy-8-trifluoromethyldibenzo[b,d]furan-1-carboxamide

A suspension of intermediate 12 (100 mg, 0.00413 mol) in a mixture ofbenzene (2 ml) and-freshly distilled thionyl chloride (2 ml) was heatedto reflux temperature for 4 h. The excess thionyl chloride was removedunder vacuum to get the corresponding acid chloride.

To a solution of 4-aminopyridine (65 mg, 0.0.794 mmol) anddiisopropylethylamine (0.3 ml) in dry TB (3 ml) was added a solution ofabove acid chloride (0.645 mmol) in dry THF (3 ml). The reaction mixturewas stirred at room temperature for 1 h. The reaction mixture wasdiluted with water (10 ml) and extracted with ethyl acetate (10 ml×3).The ethyl acetate extract was concentrated under reduced pressure andthe residue was purified by silica gel chromatography using 24%acetone-chloroform as the eluent to obtain 45 mg ofN-(pyrid-4-yl)-4-difluoromethoxy-8-trifluoromethyldibenzo[b,d]furan-1-carboxamide as a white solid; mp: 228° C.

IR (KBr) 3245, 3075, 2988, 1685, 1590, 1519, 1508, 1355, 1331, 1297,1272, 1196, 1120, 1096, 822 cm ⁻¹.

¹H NMR (300 MHz, DMSO) δ 7.60 (t, 1H, J=72.6 Hz) 7.67 (d, 1H, J=8.4 Hz),7.82 (d, 2H, J=6.2 Hz), 7.95 (dd, 1H, J=8.4 Hz, 1.8 Hz), 8.01 (d, 2H,J=8.7 Hz), 8.52 (d, 2H, J=5.4 Hz), 8.69 (s, 1H), 11.06 (s, 1H).

EXAMPLE 15 N-(pyrid-4-yl)-4-difluoromethoxy-8-trifluoromethyldibenzo[b,d]furan-1-carboxamide-N1-oxide

A suspension ofN-pyrid-4-yl)-4-difluoromethoxy-8-trifluoromethoxy-dibenzo[b,d]furan-1-carboxamide(100 mg, 0.236 mmol) (example 15) and m-chloroperbenzoic acid (50-55%)(163 mg, 0.947 mmol) in chloroform (5 ml) was stirred at roomtemperature for 18 h. Chloroform was evaporated and the resulting solidwas washed with saturated sodium bicarbonate solution, water, dried andpurified by column chromatography using 8% methanol-chloroform as theeluent to give 40 mg ofN-(pyrid-4-yl)-4-difluoromethoxy-8-trifluoromethyl-dibenzo[b,d]furan-1-carboxamide-N1-oxideas white solid; mp: 257° C. (dec).

IR(KBr): 2925, 2854, 1692, 1611, 1510, 1487, 1385, 1356, 1322, 1278,1214, 1197, 1178, 1119, 1055, 1036, 848, 820, 797, 688 cm⁻¹.

¹H-NMR (300 MHz, DMSO) δ 7.60 (t, 1H, J=72.6 Hz), 7.67 (d, 1H, J=8.4Hz), 7.85 (d, 2H, J=7.2 Hz), 7.96 (m, 2H), 8.09 (d, 1H, J=8.4 Hz), 8.21(d, 2H, J=6 Hz), 8.73 (s,1H), 11.15 (s,1H).

EXAMPLE 16 N-(pyrid-3-yl)-4-difluoromethoxy-8-trifluoromethyldibenzo[b,d]furan-1-carboxamide

A suspension of intermediate 12 (100 mg, 0.00413 mol) in a mixture ofbenzene (2 ml) and freshly distilled thionyl chloride (2 ml) was heatedto reflux temperature for 4 h. The excess thionyl chloride was removedunder vacuum to get the corresponding acid chloride.

To a solution of 3-aminopyridine (26 mg, 0.317 mmol) anddiisopropylethylamine (0.2 ml) in dry THF (5 ml) was added a solution ofabove acid chloride (0.289 mmol) in dry THF (5 ml). The reaction mixturewas stirred at room temperature for 12 h. The reaction mixture wasdiluted with water (10 ml) and extracted with ethyl acetate (10 ml×3).The ethyl acetate extract was concentrated under reduced pressure andthe residue was purified by silica gel chromatography using 20%acetone-chloroform as the eluent to obtain 60 mg ofN-(pyrid-3-yl)-4-difluoromethoxy-8-trifluoromethyldibenzo[b,d]furan-1-carboxamide as a white solid; mp: 235-236° C.

IR (KBr): 3273, 1652, 1586, 1529, 1509, 1413, 1423, 1325, 1284, 1270,1169, 1134, 1121, 1046, 828, 800, 705 cm⁻¹.

¹H NMR (300 MHz, DMSO) δ; 7.45 (m, 1H), 7.6 (t, 1H, J=85.5 Hz), 7.65 (d,1H, J=9 Hz), 8.00 (m, 2H, J=6 Hz), 8.1 (d, 1H), 8.25 ((d, 1H), 8.36(brs,1H), 8.73 (s, 1H), 8.93 (s, 1H), 10.91(s, 1H)

EXAMPLE 17 N-(pyrid-3-yl)-4-difluoromethoxy-8-trifluoromethyldibenzo[b,d]furan-1-carboxamide-N1-oxide

A suspension ofN-(pyrid-3-yl)-difluoromethoxy-8-trifluoromethoxy-dibenzo[b,d]-furan-1-carboxamide(40 mg, 0.094 mmol) (example 17) and m-chloroperbenzoic acid (50-55%)(65 mg, 0.379 mmol) in chloroform (5 ml) as stirred at room temperaturefor 12 h. Chloroform was evaporated and the resulting solid was washedwith saturated sodium bicarbonate solution, water, dried and purified bycolumn chromatography using 8% methanol-chloroform as the eluent to give12 mg of N-(pyrid-3-yl)-4-difluoromethoxy-8-trifluoromethyldibenzo[b,d]furan-1-carboxamide-N1-oxide as white solid; mp: 225-226° C.

IR (KBr); 3181, 3097, 3030, 2923, 1682, 1578, 1493, 1416, 1385, 1325,1278, 1205, 1165, 1143, 1118, 1090, 1040, 1053, 849, 824, 672 cm⁻¹.

¹HNMR (300 MHz, DMSO) δ 7.46 (t, 1H), 7.60 (t, 1H, J=72.6 Hz), 7.69(q,2H), 8.01 (m, 4H),8.73 (s,1H), 8.83 (s,1H), 11.03 (s,1H).

EXAMPLE 18 N-(pyrid-2-yl)-4-difluoromethoxy-8-trifluoromethyldibenzo[b,d]furan-1-carboxamide

A suspension of intermediate 12 (100 mg, 0.00413 mol) in a mixture ofbenzene (2 ml) and freshly distilled thionyl chloride (2 ml) was heatedto reflux temperature for 4 h. The excess thionyl chloride was removedunder vacuum to get the corresponding acid chloride.

A solution of 2-aminopyridine (47 mg, 0.578 mmol) in THF (2.5 ml) wasadded dropwise to a pre-washed suspension of sodium hydride (27 mg, 2.0equiv., 0.57 mmol, 60% oil dispersion) in THF (2.5 ml) at −10° C. Apre-cooled solution of above acid chloride (0.289 mmol) in THF (2 ml)was added, all at once, to the reaction mixture and the contents werestirred at 20° C. for 60 min. The reaction was quenched with brine,diluted with water and extracted with ethyl acetate. The organic extractwas washed with water, 5% hydrochloric acid, 5% sodium bicarbonate andbrine solution. The organic solvent was distilled off in vacuo and theresidue was purified by silica-gel chromatography using 5%acetone-chloroform as eluent to obtainN-(pyrid-2-yl)-4-difluoromethoxy-8-trifluoromethyldibenzo[b,d]furan-1-carboxamide as a white solid (18 mg); mp: 169-170°C.

IR(KBr):3293, 3023, 1655, 1596, 1577, 1529, 1506, 1437, 1399, 1355,1325, 1315, 1267, 1147, 1113, 1056, 823, 774, 611 cm⁻¹.

¹HNMR (300 MHz, DMSO) δ 7.22 (t, 1H, J=7.2 Hz), 7.58 (t,1H, J=77.7),7.606 (s,1H), 7.947 (m, 3H), 8.08 (d, 1H, J=8.7 Hz), 8.26 (d, 1H, J=6Hz), 8.41(d,1H, J=6 Hz) 8.71 (s,1H).

EXAMPLE 19 N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxydibenzo[b,d]furan-1-carboxamide

A suspension of intermediate 16 (100 mg, 0.00413 mol) in a mixture ofbenzene (2 ml) and freshly distilled thionyl chloride (2 ml) was heatedto reflux temperature for 4 h. The excess thionyl chloride was removedunder vacuum to get the corresponding acid chloride.

To a pre-washed suspension of sodium hydride (29.0 mg, 2.5 equiv., 0.73mmol, 60% oil dispersion) in DMF (2.5 ml) was added dropwise a solutionof 4-amino-3,5-dichloropyridine (47 mg, 0.29 mmol) in DMF (2.5 ml) at−10° C. A pre-cooled solution of above acid chloride in THF (2.5 ml) wasadded, all at once, to the reaction mixture and the contents werestirred at −10° C. for 30 min. The reaction was quenched with brine,diluted with water and extracted with ethyl acetate. The organic layerwas washed with water, 5% HCl, 5% sodium bicarbonate and brine solution.The solvent was evaporated and the resulting crude solid was purified bysilica-gel column chromatography using 5% ethyl acetate-chlorofrom aseluent to obtain N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxydibenzo[b,d]furan-1-carboxamide as a white solid (25 mg); mp: 270° C.

IR (KBr) 3195, 2921, 2851, 1661, 1494, 1381, 1282, 1149, 1029, 755 cm⁻¹.

¹H NMR (300 Mz, CDCl₃) δ 6.93 (t, 1H, J=72 Hz), 7.55 (m, 2 H), 7.66 (m,2 H), 7.81 (d, 1H, J=8.4 Hz), 8.47 (d, 1H, J=8.4 Hz), 8.61 (s, 2H).

EXAMPLE 20 N-(pyrid-4-yl)-4-difluoromethoxydibenzo[b,d]furan-1-carboxamide

A suspension of intermediate 16 (100 mg, 0.00413 mol) in a mixture ofbenzene (2 ml) and freshly distilled thionyl chloride (2 ml) was heatedto reflux temperature for 4 h. The excess thionyl chloride was removedunder vacuum to get the corresponding acid chloride.

To a solution of 4-aminopyridine (42 mg, 0.452 mmol) anddiisopropylethyl amine (68 mg, 0.67 mmol) in dry THF (5 ml) was added asolution of above acid chloride (0.452 mmol) in dry THF (5 ml). Thereaction mixture was sired at room temperature for 5 h. The reactionmixture was diluted with water (10 ml) and extracted with ethyl acetate(10 ml×3). The ethyl acetate extract was concentrated under reducedpressure and the residue was purified by silica gel chromatography using15% acetone-chloroform as the eluent to obtain 80 mg ofN-(pyrid-4-yl)-4-difluoromethoxy-dibenzo[b,d]furan-1-carboxamide as awhite solid; mp: 230° C.

IR (KBr): 3218, 2956, 2879, 1678, 1642, 1549, 1511, 1448, 1397, 1298,1200, 1130, 993, 828, 754, 645 cm⁻¹

¹H NMR (300 MHz, DMSO) δ 7.56 (t, 1H, J=72 Hz), 7.45 (t, 1H, J=7.5 Hz),7.62 (m, 2H), 7.81 (1H, m), 8.20 (1H, d, J=7.8 Hz), 8.52 (1H, d, J=5.4Hz), 11.04 (1H, s).

EXAMPLE 21 N-(pyrid-4-yl)-4-difluoromethoxydibenzo[b,d]furan-1-carboxamide-N1-oxide

A suspension ofN-(pyrid-4-yl)-4-difluoromethoxy-dibenzo[b,d]furan-1-carboxamide (50 mg,0.14 mmol) (example 21) and m-chloroperbenzoic acid (50-55%) (120 mg,0.70 mmol) in chloroform (10 ml) was stirred at room temperature for 16h. Chloroform was evaporated and the resulting solid was stirred insaturated sodium bicarbonate solution, filtered, dried and purified bycolumn chromatography using 40% acetone-chloroform as the eluent to give30 mg ofN-(pyrid-4-yl)-4-difluoromethoxy-dibenzo[b,d]furan-1-carboxamide-N1-oxideas white solid; mp: 244° C.

IR (KBr): −3393, 2790, 1677, 1509, 1487, 1394, 1278, 1198, 1111, 1052,852, 756 cm⁻¹

¹H NMR (300 MHz, DMSO) δ 7.42 (t, 1H, J=7.5 Hz), 7.563 (t, 1H, J=72 Hz),7.62 (m, 2H), 7.72-7.85 (m, 4H), 8.19-8.25 (m,3H), 11.14 (s, 1H).

EXAMPLE 22 N-(pyrid-3-yl)-4-difluoromethoxydibenzo[b,d]furan-1-carboxamide

A suspension of intermediate 16 (100 mg, 0.00413 mol) in a mixture ofbenzene (2 ml) and freshly distilled thionyl chloride (2 ml) was heatedto reflux temperature for 4 h. The excess thionyl chloride was removedunder vacuum to get the corresponding acid chloride.

To a solution of 3-aminopyridine (42 mg, 0.452 mmol) anddiisopropylethylamine (68 mg, 0.679 mmol) in dry THF (5 ml) was added asolution of above acid chloride (0.452 mmol) in dry THF (5 ml). Thereaction mixture was stirred at room temperature for 4 h. The reactionmixture was diluted with water (20 ml) and extracted with ethyl acetate(10 ml×3). The ethyl acetate extract was concentrated under reducedpressure and the residue was purified by silica gel chromatography using15% acetone-chloroform as the eluent to obtain 100 mg ofN-(pyrid-3-yl)-4-difluoromethoxy-dibenzo[b,d]furan-1-carboxamide as awhite solid; mp: 209-211° C.

IR (KBr): 3210, 2954, 2868, 1671, 1152, 5496, 1509, 1442, 1387, 1292,1205, 1134, 995, 830, 748, 642 cm⁻¹

¹H NMR (300 MHz, DMSO) δ 7.56 (t, 1H, J=72 Hz), 7.39 (m, 2H), 7.82 (t,1H, J=6.0 Hz), 8.261 (1H, m, J=7.2 Hz), 8.35 (1H, d, J=4.5 Hz), 8.95(1H, s), 10.88 (1H, s).

EXAMPLE 23 N-(pyrid-3-yl)-4-difluoromethoxydibenzo[b,d]furan-1-carboxamide-N1-oxide

A suspension ofN-(pyrid-3-yl)-4-difluoromethoxy-dibenzo[b,d]furan-1-carboxamide (50 mg,0.14 mmol) (example 23) and m-chloroperbenzoic acid (50-55%) (120 mg,0.704 mmol) in chloroform (10 ml) was stirred at room temperature for 12h. Chloroform was evaporated and the resulting solid was stirred insaturated sodium bicarbonate solution, filtered, dried and purified bycolumn chromatography using 40% acetone-chloroform as the eluent to give25 mg of ofN-(pyrid-3-yl)-4-difluoromethoxy-dibenzo[b,d]furan-1-carboxamide-N1-oxideas white solid; mp: 252° C. (dec)

IR (KBr): 3243, 3057, 2921, 1677, 1575, 1450, 1304, 1281, 1198, 1042,997, 844, 740 cm⁻¹

¹H NMR (300 MHz, DMSO) δ 7.43 (t, 1H, J=8.1 Hz), 7.56 (t, 1H, J=72 Hz),7.57-7.70 (m, 4H), 7.79-7.82 (m, 2H), 8.04(d,1H, J=5.4 Hz), 8.24 (d,1H,J=8.4 Hz), 8.86 (s,1H), 11.01 (s,1H).

EXAMPLE 24 N-(5-chloropyrid-2-yl)-4-difluoromethoxydibenzo[b,d]furan-1-carboxamide

A suspension of intermediate 16(100 mg, 0.00413 mol) in a mixture ofbenzene (2 ml) and freshly distilled thionyl chloride (2 ml) was heatedto reflux temperature for 4 h. The excess thionyl chloride was removedunder vacuum to get the corresponding acid chloride.

To a pre-washed suspension of sodium hydride (28 mg, 2.5 equiv., 0.71mmol, 60% oil dispersion) in DMF (2.5 ml) was added dropwise a solutionof 2-amino-5-chloropyridine (92 mg, 0.71 mmol) in DMF (2.5 ml) at −10°C. A pre-cooled solution of above acid chloride (0.35 mmol) in THF (2.5ml) was added, all at once, to the reaction mixture and the contentswere stirred at −10° C. for 30 min. The reaction was quenched withbrine, diluted with water and extracted with ethyl acetate. The organiclayer was washed with water, 5% HCl, 5% sodium bicarbonate and brinesolution. The solvent was evaporated and the resulting crude solid waspurified by silica-gel column chromatography using 20% ethylacetate-petroleum ether as eluent to obtainN-(5-chloropyrid-2-yl)-4-difluoromethoxy dibenzo[b,d]furan-1-carboxamideas a white solid (10 mg); mp: 155-157° C.

IR (KBr): 3256, 2849, 1659, 1571, 1522, 1503, 1450, 1381, 1249, 1282,1221, 1197, 1166, 1150, 1132, 1110, 1034, 1011, 754 cm⁻¹.

¹H NMR: (300 MHz, DMSO): δ 7.32-7.64 (m, 3H), 7.56 (t, 1H, J=72 Hz),7.79-7.84 (m, 2H.), 8.02 (d, 1H, J=6.3 Hz), 8.22 (d, 1H, J=7.8 Hz), 8.35(d, 1H, J=9 Hz), 8.45(s, 1H), 11.38 (s,1H).

EXAMPLE 25 N-(3,5-dichloropyrid-4-yl)-4-cyclopropylmethoxydibenzo[b,d]furan-1-carboxamide

A suspension of intermediate 21 (50 mg, 0.177 mmol) in a mixture ofbenzene (2 ml) and freshly distilled thionyl chloride (0.5 ml) washeated to reflux temperature for 3 h The excess thionyl chloride wasremoved under vacuum to get the corresponding acid chloride.

To a pre-washed suspension of sodium hydride (18 mg, 2.5 equiv., 0.443mmol, 60% oil dispersion) in DMF (2 ml) was added dropwise a solution of4-amino-3,5-dichloropyridine (28 mg, 0.17 mmol) in DMF (2 ml) at −10° C.A pre-cooled solution of above acid chloride in THF (5 ml) was added,all at once, to the reaction mixture and the contents were stirred at−10° C. for 30 min. The reaction was quenched with brine, diluted withwater and extracted with ethyl acetate. The organic layer was washedwith water, 5% HCl, 5% sodium bicarbonate and brine solution.Evaporation of solvent and purification of the crude solid by silica gelcolumn chromatography using 10% acetone-chloroform as eluent providedN-(3,5-dichloropyrid-4-yl)-4-cyclopropylmethoxydibenzo[b,d]furan-1-carboxamide as a white solid (38 mg); mp: 242° C.

IR (KBr) 3202, 2922, 2853, 1665, 1552, 1484, 1396, 1281, 1198, 1095,903, 835, 750, 672 cm⁻¹.

¹H NMR (300 MHz, DMSO) 0.452 (m, 2H), 0.66 (m, 2H), 1.38 (m, 1H), 4.18(d, 2H, J=7.5 Hz), 7.31 (d, 1H, J=9.0 Hz), 7.36 (d, 1H, J=7.5 Hz), 7.55(t, 1H, J=6.9 Hz), 7.8 (d, 1H, J=8.4 Hz), 7.88 (d, 1H, J=8.4 Hz), 8.42(d, 1H, J=9.5 Hz), δ 8.78 (s,1H), δ 10.8 (s,1H).

EXAMPLE 26 N-(3,5-dichloropyrid-4-yl)-4-cyclopropylmethoxydibenzo[b,d]furan-1-carboxamide-N1-oxide

A suspension ofN-(3,5-dichloropyrid-4-yl)-4-cyclopropylmethoxy-dibenzo[b,d]furan-1-carboxamide(370 mg, 0.936 mmol) (example 26) and m-chloroperbenzoic acid (50-55%)(1.0 gm, 4.68 mmol) in chloroform (20 ml) was stirred at roomtemperature for 12 h. The reaction contents were washed with saturatedsodium bicarbonate and water. The organic solvent was distilled of invacuo and the residue was purified by column chromatography using 30%acetone-chloroform as the eluent to give 200 mg ofN-(3,5-dichloropyrid-4-yl)-4-cyclopropylmethoxy-dibenzo[b,d]furan-1-carboxamide-N1-oxideas white solid; mp: 263-265° C.

IR (KBr) 3228, 3061, 1662, 1576, 1476, 1395, 1280, 1198, 1097, 895, 750cm⁻¹

¹H NMR (300 MHz,CDCl₃) δ 0.452 (m,2H, 0.66 (m, 2H), 1.38 (m, 1H), 4.13(d, 2H, J=7.5 Hz), 7.21 (d, 1H, J=8.7 Hz), 7.40 (t,1H, J=7.2 Hz), 7.65(t, 1H, J=6.9 Hz), 7.79 (d,1H, J=8.4 Hz), 7.96 (d,1H, J=8.1Hz), 8.41 (d,1H, J=7.2 Hz), 8.75 (d, 2H, J=7.5 Hz), 10.62 (s,1H).

EXAMPLE 27 N-(pyrid-4-yl)-4-cyclopropylmethoxydibenzo[b,d]furan-1-carboxamide

A suspension of intermediate 21 (50 mg, 0.177 mmol) in a mixture ofbenzene (2 ml) and fleshly distilled thionyl chloride (0.5 ml) washeated to reflux temperature for 3 h. The excess thionyl chloride wasremoved under vacuum to get the corresponding acid chloride.

To a solution of 4-aminopyridine (33 mg, 0.354 mmol) anddiisopropylethylamine (54 mg) in dry THF (3 ml) was added a solution ofabove acid chloride (0.354 mmol) in dry THF (3 ml). The reaction mixturewas stirred at room temperature for 2 h. The reaction mixture wasdiluted with water (10 ml) and extracted with ethyl acetate (10 ml×3).The ethyl acetate extract was concentrated under reduced pressure andthe residue was purified by silica gel chromatography using 20%acetone-chloroform as the eluent to obtain 65 mg ofN-(pyridyl)-cyclopropylmethoxy-dibenzo[b,d]furan-1-carboxamide as awhite solid; mp: 243-244° C.

IR (KBr) 3278, 2925, 1657, 1583, 1487,1396, 1282, 1195, 1094, 993, 886,781, 631 cm⁻¹

¹H NMR (300 MHz, DMSO) δ 0.452 (m, 2H), δ 0.66 (m, 2H), 1.38 (m, 1H),4.15 (d, 2H, J=6.9 Hz), 7.26 (d, 1H, J=8.4 Hz), 7.37 (t, 1H, J=7.2 Hz),7.56 (t, 1H, J=6.9 Hz), 7.73-7.81 (m, 4H, 8.29 (d, 1H, J=7.5 Hz), 8.49(d, 2H, J=6.3 Hz), 10.84 (s,1H).

EXAMPLE 28 N-(pyrid-4-yl)-4-cyclopropylmethoxydibenzo[b,d]furan-1-carboxamide-N1-oxide

A suspension ofN-(pyrid-4-yl)-4-cyclopropylmethoxy-dibenzo[b,d]furan-1-carboxamide (50mg, 0.139 mmol) (example 28) and m-chloroperbenzoic acid (50-55%) (120mg, 0.698 mmol) in chloroform (10 ml) was stirred at room temperaturefor 12-16 h. The reaction contents were washed with saturated sodiumbicarbonate and water. The organic solvent was distilled of in vacuo andthe residue was purified by column chromatography using 40%acetone-chloroform as the eluent to give 25 mg ofN-(pyrid-4-yl)-4-cyclopropylmethoxy-dibenzo[b,d]furan-1-carboxamide-N1-oxideas white solid; mp: 266-268° C.

IR (KBr) 3228, 3061, 1662, 1576, 1476, 1395, 1280, 1198, 1097, 895, 750cm⁻¹

¹H NMR (300 MHz, DMSO) δ 0.452 (m, 2H), 0.66 (m, 2H), 1.38 (m, 1H), 4.13(d, 2H, J=7.5 Hz), 7.21 (d, 1H, J=8.7 Hz), 7.40 (t, 1H, J=7.2 Hz), 7.65(t, 1H, J=6.9 Hz), 7.79 (d, 1H, J=8.4 Hz), 7.96 (d, 1H, J=8.1 Hz), 8.41(d, 1H, J=7.2 Hz), 8.75 (d, 2H, J=7.5 Hz), 10.62 (s,1H).

EXAMPLE 29 N-(pyrid-3-yl)-4-cyclopropylmethoxydibenzo[b,d]furan-1-carboxamide

A suspension of intermediate 21 (50 mg, 0.177 mmol) in a mixture ofbenzene (2 ml) and freshly distilled thionyl chloride (0.5 ml) washeated to reflux temperature for 3 h. The excess thionyl chloride wasremoved under vacuum to get the corresponding acid chloride.

To a solution of 3-aminopyridine (33 mg, 0.354 mmol) anddiisopropylethylamine (0.3 ml) in dry THF (3 ml) was added a solution ofabove acid chloride (0.0.354 mmol) ( in dry THF 3 ml). The reactionmixture was stirred at room temperature for 2 h. The reaction mixturewas diluted with water (10 ml) and extracted with ethyl acetate (10ml×3). The ethyl acetate extract was concentrated under reduced pressureand the residue was purified by silica gel chromatography using 20%acetone-chloroform as the eluent to obtain 70 mg ofN-(pyrid-3-yl)-cyclopropylmethoxy-dibenzo[b,d]furan-1-carboxamide as awhite solid; mp: 238-240° C.

IR (KBr) 3303, 2927, 2874, 1651, 1526, 1450, 1329, 1288, 1129, 1093,999, 808, 748 cm⁻¹

¹H NMR (300 MHz, DMSO) 0.452 (m, 2H), 0.66 (m, 2H), 1.38 (m, 1H), 4.1(d, 2H, J=7.2 Hz), 7.26 (d, 1H, J=8.4 Hz), 7.33-7.44 (m, 2H), 7.55 (t,1H, J=8.1 Hz), 7.73-7.80 (m, 2H), 8.24 (d, 1H, J=9.0 Hz), 831-8.33 (m,2H), 8.92 (s, 1H), 10.68 (s,1H).

EXAMPLE 30 N-(pyrid-3-yl)cyclopropylmethoxydibenzo[b,d]furan-1-carboxamide-N1-oxide

A suspension ofN-(pyrid-3-yl)-4-cyclopropylmethoxy-dibenzo[b,d]furan-1-carboxamide (15mg, 0.139 mmol) (example 30) and m-chloroperbenzoic acid (50-55%) (120mg, 0.698 mmol) in chloroform (10 ml) was stirred at room temperaturefor 12 h. The reaction contents were washed with saturated sodiumbicarbonate and water. The organic solvent was distilled of in vacuo andthe residue was purified by column chromatography using 40%acetone-chloroform as the eluent to give 30 mg ofN-(pyrid-3-yl)-4-cyclopropylmethoxy-dibenzo[b,d]furan-1-carboxamide-N-oxideas white solid; mp: 272-275° C.

IR (KBr): 3232, 3069, 2872, 1673, 1571, 1417, 1277, 1154, 1095, 1006,840, 743 cm⁻¹

¹H NMR (300 MHz, DMSO) δ 0.452 (m, 2H), 0.66 (m, 2H), 1.38 (m, 1H), 4.13(d, 2H, J=7.5 Hz), 7.21 (d, 1H, J=8.7 Hz), 7.35-7.58 (m, 2H), 7.68-7.81(m, 4H), 8.02 (d,1H, J=6.0 Hz), 8.32 (d,1H, J=7.8 Hz), 8.86 (s, 1H),10.82 (s, 1H).

EXAMPLE 31 N-(3,5-dichloropyrid-4-yl)-4-isopropyloxydibenzo[b,d]furan-1-carboxamide

A suspension of intermediate 23 (50 mg, 0.177 mmol) in a mixture ofbenzene (2 ml) and freshly distilled thionyl chloride (0.5 ml) washeated to reflux temperature for 3 h. The excess thionyl chloride wasremoved under vacuum to get the corresponding acid chloride.

To a pre-washed suspension of sodium hydride (30.0 mg, 2.0 equiv., 0.74mmol, 60% oil dispersion) in DMF (3 ml) was added dropwise a solution of4-amino-3,5-dichloropyridine (60 mg, 0.37 mmol) in DMF (3 ml) at −10° C.A pre-cooled solution of above acid chloride in THF (2 ml) was added,all at once, to the reaction mixture and the contents were stirred at−10° C. for 30 min. The reaction was quenched with brine, diluted withwater and extracted with ethyl acetate. The organic layer was washedwith water, 5% HCl, 5% sodium bicarbonate and brine solution.Evaporation of solvent and purirication of the crude solid by silica gelcolumn chromatography using 15% ethyl acetate-chloroform as eluentprovided N-(3,5-dichloropyrid-4-yl)-4-isopropylmethoxydibenzo[b,d]furan-1-carboxamide as a white solid (100 mg); mp: 209-211°C.

IR(KBr) 3193, 2973, 1665, 1602, 1555, 1452, 1387, 1279, 1110, 1093, 964,802, 751, 682 cm⁻¹

¹H NMR (300 MHz, DMSO) δ 1.43 (d, 6H, J=5.7 Hz), δ 5.06 (m, 1H), 7.35(t, 1H, J=9.3 Hz), 7.36 (s, 1H), 7.54 (t, 1H, J=6.9 Hz), 7.77 (d, 1H,J=8.1 Hz), 7.8 (d, 1H, J=8.4 Hz), 8.41 (d, 1H, J=7.2 Hz),), 8.78 (s,1H),), 10.8 (s, 1H).

EXAMPLE 32 N-(3,5-dichloropyrid-4-yl)-4-isopropyloxydibenzo[b,d]furan-1-carboxamide-N1-oxide

A suspension ofN-(3,5-dichloropyrid-4-yl)-4-isopropyloxy-dibenzo[b,d]furan-1-carboxamide(60 mg, 0.144 mmol) (example 32) and m-chloroperbenzoic acid (50-55%)(120 mg, 0.722 mmol) in chloroform (10 ml) was stirred at roomtemperature for 12 h. The reaction contents were washed with saturatedsodium bicarbonate and water. The organic solvent was distilled of invacuo and the residue was purified by column chromatography using 30%acetone-chloroform as the eluent to give 57 mg ofN-(3,5dichlorpyrid-4-yl)-4-isopropyloxy-dibenzo[b,d]furan-1-carboxamide-N1-oxideas white solid; mp: 247-248° C.

IR (KBr) 3213, 2978, 1655, 1574, 1474, 1384, 1280, 1127, 1098, 988, 824,748 cm⁻¹

¹H NMR (300 MHz, DMSO) δ 1.41(d, 6H, J=5.7 Hz), 5.0 (m, 1H), 7.35 (m,2H), 7.5 (t, 1H, J=6.9 Hz), 7.76 (d, 1H, J=8.4 Hz), 7.85 (d, 1H, J=8.4Hz), 8.4 (d, 1H, J=7.5 Hz), 8.7 (s, 1H), 10.62 (s, 1H).

EXAMPLE 33 N-(pyrid-4-yl)-4-isopropyloxy dibenzo[b,d]furan-1-carboxamide

A suspension of intermediate 23 (50 mg, 0.177 mmol) in a mixture ofbenzene (2 ml) and freshly distilled thionyl chloride (0.5 ml) washeated to reflux temperature for 3 h The excess thionyl chloride wasremoved under vacuum to get the corresponding acid chloride.

To a solution of 4-aminopyridine (35 mg, 0.37 mmol) anddiisopropylethylamine (60 mg. 0.55 mmol) in dry THF (3 ml) was addedabove solution of acid chloride (0.37 mmol) in dry THF (3 ml). Thereaction mixture was stirred at room temperature for 1 h. The reactionmixture was diluted with water (10 ml) and extracted with ethyl acetate(10 ml×3). The ethyl acetate extract was concentrated under reducedpressure and the residue was purified by silica gel chromatography using20% acetone-chloroform as the eluent to obtain 90 mg ofN-(pyrid-4-yl)-isopropyloxy-dibenzo[b,d]furan-1-carboxamide as a whitesolid; mp: 151° C. (dec)

IR (KBr) 3278, 2925, 1657, 1583, 1487, 1396, 1282, 1195, 1094, 993, 886,781, 631 cm⁻¹

¹H NMR (300 MHz, DMSO) δ 0.452 (m,2H), 0.66 (m, 2H), 1.38 (m, 1H), 4.15(d, 2H, J=6.9 Hz), 7.26 (d, 1H, J=8.4 Hz), 7.37 (t, 1H, J=7.2 Hz), 7.56(t, 1H, J=6.9 Hz), 7.73-7.81 (m, 4H), 8.29 (d, 1H, J=7.5 Hz), 8.49 (d,2H, J=6.3 Hz), 10.84 (s, 1H).

EXAMPLE 34 N-(pyrid-4-yl)-4-isopropyloxydibenzo[b,d]furan-1-carboxamide-N1-oxide

A suspension of N-pyrid-4-yl)-4-isopropyloxydibenzo[b,d]furan-1-carboxamide (50 mg, 0.144 mmol) (example 34) andm-chloroperbenzoic acid (50-55%) (125 mg, 0.722 mmol) in chloroform (10ml) was stirred at room temperature for 12 h. The reaction contents werewashed with saturated sodium bicarbonate and water. The organic solventwas distilled of in vacuo and the residue was purified by columnchromatography using 40% acetone-chloroform as the eluent to give 27 mgof N-pyrid-4-yl)-4-isopropyloxy-dibenzo[b,d]furan-1-carboxamide-N1-oxideas white solid, mp: 247-248° C. (dec)

IR (KBr): 3061, 2918, 2851, 1682, 1594, 1487, 1311, 1293, 1194, 1036,959, 844, 767 cm⁻¹

¹H NMR (300 MHz, DMSO) δ 1.43 (d, 6H, J=5.7 Hz), 5.06 (m, 1H), 7.34 (m,2H), 7.55 (t, 1H, J=6.6 Hz), 7.72-7.86 (m, 5H), 8.18 (d, 2H, J=7.8 Hz),8.39 (d, 1H, J=7.8 Hz), 10.95 (s, 1H).

EXAMPLE 35 N-(pyrid-3-yl)-4-isopropyloxy dibenzo[b,d]furan-1-carboxamide

A suspension of intermediate 23 (50 mg, 0.177 mmol) in a mixture ofbenzene (2 ml) and freshly distilled thionyl chloride (0.5 ml) washeated to reflux temperature for 3 h. The excess thionyl chloride wasremoved under vacuum to get the corresponding acid chloride.

To a solution of 3-aminopyridine (35 mg, 0.37 mmol) and diisopropylethylamine (60 mg, 0.55 mmol) in dry THF (3 ml) was added above solution ofacid chloride (0.37 mmol) in dry THF (3 ml). The reaction mixture wasstirred at room temperature for 1 h. The reaction mixture was dilutedwith water (10 ml) and extracted with ethyl acetate (10 ml×3). The ethylacetate extract was concentrated under reduced pressure and the residuewas purified by silica gel chromatography using 20% acetone-chloroformas the eluent to obtain 80 mg ofN-(pyrid-3-yl)-isopropyloxy-dibenzo[b,d]furan-1-carboxamide as a whitesolid; mp: 209-211° C.

IR (KBr): 3283, 2925, 1657, 1525, 1486, 1410, 1293, 1277, 1106, 1092,994, 884, 788, 671 cm⁻¹

¹H NMR (300 MHz, DMSO) δ 1.43 (d, 6H, J=5.7 Hz), 5.06 (m, 1H), 7.31-7.45(m, 3H), 7.45 (t, 1H, J=7.1 Hz), 7.76 (m, 2H), 7.29 (m, 3H), 8.94(s,1H), 10.7 (s, 1H).

EXAMPLE 36 N-(pyrid-3-yl)-4-isopropyloxydibenzo[b,d]furan-1-carboxamide-N1-oxide

A suspension ofN-(pyrid-3-yl)-4isopropyloxy-dibenzo[b,d]furan-1-carboxamide (50 mg,0.144 mmol) (example 36) and m-chloroperbenzoic acid (50-55%) (125 mg,0.722 mmol) in chloroform (10 ml) was stirred at room temperature for 12h. The reaction contents were washed with saturated sodium bicarbonateand water. The organic solvent was distilled off in vacuo and theresidue was purified by column chromatography using 40%acetone-chloroform as the eluent to give 30 mg ofN-pyrid-3-yl)-4-isopropyloxy-dibenzo[b,d]furan-1-carboxamide-N1-oxide aswhite solid; mp: 242° C.(dec).

IR (KBr): 3081, 2975, 1683, 1546, 1385, 1278, 1156, 1093, 970, 813, 745cm⁻¹

¹H NMR (300 MHz, DMSO) δ 1.43 (d, 6H, J=5.7 Hz), 5.00 (m, 1H), 7.32-7.44(m, 3H), 7.56 (t, 1H, J=8.1 Hz), 7.68-7.79 (m, 3H), 8.01 (d, 1H, J=5.4Hz), 8.30 (d, 1H, J=7.8 Hz), 8.62 (s, 1H), 10.82(s, 1H).

EXAMPLE 37 N-(3,5-dichloropyrid-4-yl)-4-benzyloxydibenzo[b,d]furan-1-carboxamide

A suspension of intermediate 25 (250 mg, 0.786 mmol) in a mixture ofbenzene (2 ml) and freshly distilled thionyl chloride (2.0 ml) washeated to reflux temperature for 3 h. The excess thionyl chloride wasremoved under vacuum to get the corresponding acid chloride.

To a pre-washed suspension of sodium hydride (75 mg, 2.0 equiv., 1.57mmol, 60% oil dispersion) in DMF (3 ml) was added dropwise a solution of4-amino-3,5-dichloropyridine (128 mg, 0.78 mmol) in DMF (3 ml) at −10°C. A pre-cooled solution of above acid chloride in THF (5 ml) was added,all at once, to the reaction mixture and the contents were stirred at−10° C. for 30 min. The reaction was quenched with brine, diluted withwater and extracted with ethyl acetate. The organic layer was washedwith water, 5% HCl, 5% sodium bicarbonate and brine solution Evaporationof solvent and purification of the crude solid by silica gel columnchromatography using 5% ethyl acetate-chloroform as eluent providedN-(3,5-dichloropyrid-4-yl)-4-benzyloxy dibenzo[b,d]furan-1-carboxamideas a white solid (10 mg); mp: 269-270° C. (dec).

IR (KBr): 3376, 3244, 2928, 1664, 1603, 1556, 1484, 1399, 1383, 1278,1195, 1092, 999, 830, 808, 754 cm⁻¹.

¹HNMR (300 MHz, DMSO) δ 5.45 (s, 2H), 7.38(m, 5H), 7.45 (m, 3H), 7.77(d, 1H, J=9 Hz), 7.86 (d, 1H, J=8.4 Hz), 8.41(d, 1H, J=9 Hz), 8.77 (s,2H), 10.81(s, 1H).

EXAMPLE 38 N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-nitrodibenzo[b,d]furan-1-carboxamide

A suspension of intermediate 29 (50 mg, 0.177 mmol) in a mixture ofbenzene (2 ml) and freshly distilled thionyl chloride (0.5 ml) washeated to reflux temperature for 3 h. The excess thionyl chloride wasremoved under vacuum to get the corresponding acid chloride.

To a pre-washed suspension of sodium hydride (52 mg, 2.5 equiv., 1.3mmol, 60% oil dispersion) in DMF (2 ml) was added dropwise a solution of4-amino-3,5-dichloropyridine (93 mg, 0.52 mmol) in DMF (2 ml) at −10° C.A pre-cooled solution of above acid chloride (0.52 mmol) in THF (2 ml)was added, all at once, to the reaction mixture and the contents werestirred at −10° C. for 30 min. The reaction was quenched with brine,diluted with water and filtered to give a crude solid which was washedwith ethanol to giveN-(3,5-dichloropyrid-4-yl)-4-methoxy-8-nitro-dibenzo[b,d]furan-1-carboxamideas a white solid (80 mg); mp: 315-317° C.

IR (KBr): 3245, 3092, 2845, 1662, 1614, 1581, 1554, 1519, 1483, 1461,1439, 1391, 1337, 1282, 1205, 1181, 1067 cm-¹.

¹H NMR (300 MHz, DMSO) δ 4.12 (s, 3H), 7.48 (d, 1 H, J=8.1 Hz), 8.03 (d,1H, J=8.1 Hz), 8.06 (d, 1H, J=8.4 Hz), 8.44 (dd, 1H, J=7.2 Hz), 8.81 (s,2H). 9.43 (d, 1H, J=1.2 Hz), 10.95 (s, 1H).

EXAMPLE 39 N-(pyrid-4-yl)-4-methoxy-8-nitrodibenzo[b,d]furan-1-carboxamide

A suspension of intermediate 29 (50 mg, 0.177 mmol) in a mixture ofbenzene (2 ml) and freshly distilled thionyl chloride (0.5 ml) washeated to reflux temperature for 3 h. The excess thionyl chloride wasremoved under vacuum to get the corresponding acid chloride.

To a solution of 4-aminopyridine (31 mg, 0.34 mmol) and diisopropylethylamine (0.3 ml) in dry THF (3 ml) was added a solution of above acidchloride (0.34 mmol) in dry THF (3 ml). The reaction mixture was stirredat room temperature for 1 h. The reaction mixture was diluted with water(10 ml) and extracted with ethyl acetate (10 ml×3).The ethyl acetateextract was concentrated under reduced pressure and the residue waspurified by silica gel chromatography using 20% acetone-chloroform asthe eluent to obtain 30 mg ofN-(pyrid-4-yl)-methoxy-8-nitro-dibenzo[b,d]furan-1-carboxamide as awhite solid; mp: 222° C.

IR (KBr): 3272, 2838, 1647, 1522, 1447, 1406, 1296, 1280, 1259, 1174,1100, 1019 cm⁻¹.

¹H NMR: (300 MHz, DMSO) δ 4.00 (s, 3H ), 7.22 (m, 3H), 7.50 (t, 1H,J=7.8 Hz), 7.66 (m, 2H), 7.97-7.99 (m, 2H), 8.82-8.84 (m, 2H), 10.85(s,1H).

EXAMPLE 40 N-(pyrid-3-yl)-4-methoxy-8-nitrodibenzo[b,d]furan-1-carboxamide

A suspension of intermediate 29 (50 mg, 0.177 mmol) in a mixture ofbenzene (2 ml) and freshly distilled thionyl chloride (0.5 ml) washeated to reflux temperature for 3 h. The excess thionyl chloride wasremoved under vacuum to get the corresponding acid chloride.

To a solution of 3-aminopyridine (49 mg, 0.52 mmol) and diisopropylethylamine (0.3 ml) in dry THF (3 ml) was added a solution of above acidchloride (0.52 mmol) in dry THF (3 ml). The reaction mixture was stirredat room temperature for 1 h. The reaction mixture was diluted with water(10 ml) and extracted with ethyl acetate (10 ml×3). The ethyl acetateextract was concentrated under reduced pressure and the residue waspurified by silica gel chromatography using 20% acetone-chloroform asthe eluent to obtain 20 mg ofN-(pyrid-3-yl)-methoxy-8-nitro-dibenzo[b,d]furan-1-carboxamide as awhite solid; mp: 263-266° C.

IR (KBr): 3273, 3090, 3842, 1647, 1611, 1582, 1520, 1484, 1340, 1286,1204, 1069, 703 cm⁻¹.

¹H NMR: (300 Mz, DMSO) δ 4.10 (s, 3H), 7.45 (d, 2H), 7.99 (m, 2H), 8.26(d, 1H), 8.29 (brs, 1H), 8.46 (d, 1H), 8.95 (brs, 1H), 9.37 (s, 1H),10.76 (s, 1H).

EXAMPLE 41N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-chloro-dibenzo[b,d]furan-1-carboxamide

A suspension of intermediate 31 (110 mg, 0.422 mmol) in a mixture ofbenzene (2 ml) and freshly distilled thionyl chloride (2 ml) was heatedto reflux temperature for 3-4 h The excess thionyl chloride was removedunder vacuum to get the corresponding acid chloride.

To a pre-washed suspension of sodium hydride (20 mg, 2.0 equiv., 0.844mmol, 60% oil dispersion) in DMF (3 ml) was added dropwise a solution of4-amino-3,5-dichloropyridine (68 mg, 0.42 mmol) in DMF (2 ml) at −10° C.A pre-cooled solution of above acid chloride in THF (3 ml) was added,all at once, to the reaction mixture and the contents were stirred at−10° C. for 30 min. The reaction was quenched with brine, diluted withwater and extracted with ethyl acetate. The organic layer was washedwith water, 5% HCl, 5% sodium bicarbonate and brine solution. Thesolvent was evaporated and the resulting crude solid was purified bycolumn chromatography using 40% ethyl acetate chloroform as the eluentto obtain 60 mg ofN-(3,5-dichloropyrid-4-yl)-4-methoxy-8-chloro-dibenzo[b,d]furan-1-carboxamideas a white solid; mp: 300° C.

IR (KBr): 3173, 2956, 2851, 1660, 1544, 1492, 1454, 1390, 1285, 1257,1132, 1107, 905, 806, 634 cm⁻¹

¹H NMR (300 MHz, DMSO) δ 4.05 (s, 3H), 7.38 (d, 2H, J=8.7 Hz), 7.58 (d,1H, J=9 Hz), 7.80 ( d, 1H, J=8.7 Hz), 7.95 (d, 1H, J=8.7 Hz), 8.47 (s,1H, J=2.4 Hz ), 8.79 (s, 2H), 10.87 (s, 1H).

EXAMPLE 42N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-bromo-dibenzo[b,d]furan-1-carboxamide

A suspension of intermediate 32 (120 mg, 0.403 mmol) in a mixture ofbenzene (2 ml) and freshly distilled thionyl chloride (2 ml) was heatedto reflux temperature for 3-4 h. The excess thionyl chloride was removedunder vacuum to get the corresponding acid chloride.

A solution of 4-amino-3,5-dichloropyridine (68 mg, 0.42 mmol) in DMF (3ml) at −10° C. was added to a pre-washed suspension of sodium hydride(24 mg, 2.5 equiv., 1.08 mmol, 60% oil dispersion) in DMF (3 ml)dropwise. A pre-cooled solution of above acid chloride in THF (3 ml) wasadded, all at once, to the reaction mixture and the contents werestirred at −10° C. for 30 min. The reaction was quenched with brine,diluted with water and extracted with ethyl acetate. The organic layerwas washed with water, 5% HCl, 5% sodium bicarbonate and brinesolution.The solvent was evaporated and the resulting crude solid waspurified by column chromatography using 10% acetone-chloroform as theeluent to obtain 110 mg ofN-(3,5-dichloropyrid-4-yl)-4-methoxy-8-bromo-dibenzo[b,d]furan-1-carboxamideas a white solid; mp: 308° C.

IR (KBr): 3144, 3040, 2977, 2944, 2846, 1660, 1542, 1496, 1301, 1282,1203, 1106, 1018, 914, 803, 726, 662 cm⁻¹

¹H NMR (300 MHz, DMSO) δ 4.08 (s, 3H), 7.38 (d, 1H, J=8.1 Hz), 7.73 (d,1H, J=8.7 Hz), 7.76 (d, 1H, J=6.9 Hz), 7.94 (d, 1H, J=8.7 Hz), 8.62 (s,1H, J=2.1 Hz), 8.79 (s, 2H), 10.87 (s, 1H).

EXAMPLE 43N-(pyrid-4-yl)-4-methoxy-8-bromo-dibenzo[b,d]furan-1-carboxamide

A suspension of intermediate 32 (120 mg, 0.403 mmol) (from step 2 above)in a mixture of benzene (2 ml) and freshly distilled thionyl chloride (2ml) was heated to reflux temperature for 3-4 h. The excess thionylchloride was removed under vacuum to get the corresponding acidchloride.

To a solution of 4-aminopyridine (29 mg, 0.310 mmol) anddiisopropylethyl amine (59 mg, 0.591 mmol) in dry THF (5 ml) was added asolution of above acid chloride (0.295 mmol) in dry THF (5 ml). Thereaction mixture was stirred at room temperature for 2 h. The reactionmixture was diluted with water (10 ml) and extracted with ethyl acetate(10 ml×3). The ethyl acetate extract was concentrated under reducedpressure and the residue was purified by silica gel chromatography using20% acetone-chloroform as the eluent to obtain 65 mg ofN-(pyrid-4-yl)-methoxy-8-bromo-dibenzo[b,d]furan-1-carboxamide as awhite solid; mp: 270-273° C.

IR (KBr): 3309, 3037, 2923, 2852, 1660, 1585, 1505, 1410, 1330, 1282,1256, 1181, 1106, 902, 886, 750, 654 cm⁻¹

¹H NMR (300 MHz, DMSO) δ 4.07 (s, 1H), 7.35 (d, 1H, J=8.1 Hz), 7.73 (d,1H), 7.74 (d, 1H, J=6.6 Hz), 7.79 (d, 1H, J=6.7 Hz), 7.85 (d, 1H, J=8.4Hz), 8.49 (d, 2H, J=6.3 Hz), 8.51 (s, 2H), 10.8 (s, 1H).

EXAMPLE 44N-(pyrid-3-yl)-4-methoxy-8-bromo-dibenzo[b,d]furan-1-carboxamide

A suspension of intermediate 32 (120 mg, 0.403 mmol) in a mixture ofbenzene (2 ml) and freshly distilled thionyl chloride (2 ml) was heatedto reflux temperature for 3-4 h. The excess thionyl chloride was removedunder vacuum to get the corresponding acid chloride.

To a solution of 3-aminopyridine (29 mg, 0.31 mmol) and diisopropylethylamine (59 mg, 0.591 mmol) in dry THF (5 ml) was added a solution ofabove acid chloride (0.295 mmol) in dry THF (5 ml). The reaction mixturewas stirred at room temperature for 1 h. The reaction mixture wasdiluted with water (10 ml) and extracted with ethyl acetate (10 ml×3).The ethyl acetate extract was concentrated under reduced pressure andthe residue was purified by silica gel chromatography using 30%acetone-chloroform as the eluent to obtain 45 mg ofN-pyrid-3-yl)-methoxy-8-bromo-dibenzo[b,d]furan-1-carboxamide as a whitesolid; mp: 265° C. (dec)

IR (KBr): 3257, 2924, 2853, 1645, 1602, 1525, 1483, 1409, 1390, 1284,1263, 1107, 1022, 882, 795, 705, 634 cm⁻¹

¹H NMR (300 MHz, DMSO) δ 4.07 (s, 3H), 7.35 (d, 1H, J=8.4 Hz), 7.41 (t,1H, J=8.4 Hz), 7.70 (d, 1H, J=8.7 Hz), 7.76 (d, 1H, J=8.7 Hz), 7.86 (d,1H, J=8.1 Hz), 8.23 (d, 1H, J=3.9 Hz), 8.32 (d, 1H, J=4.5 Hz), 8.55 (s,1H, J=1.8 Hz), 8.92 (s, 1H, J=2.7 Hz), 10.71 (s, 1H).

EXAMPLE 45N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-iodo-dibenzo[b,d]furan-1-carboxamide

A suspension of intermediate 33 (140 mg, 0.44 mmol) in a mixture ofbenzene (2 ml) and freshly distilled thionyl chloride (2 ml) was heatedto reflux temperature for 3-4 h. The excess thionyl chloride was removedunder vacuum to get the corresponding acid chloride.

To a pre-washed suspension of sodium hydride (26 mg, 2.5 equiv., 1.10mmol, 60% oil dispersion) in DMF (3 ml) was added dropwise a solution of4-amino-3,5-dichloropyridine (75 mg, 417 mmol) in DMF (2 ml) at −10° C.A pre-cooled solution of above acid chloride in THF (5 ml) was added,all at once, to the reaction mixture and the contents were stirred at−10° C. for 30 min. The reaction was quenched with brine, diluted withwater and extracted with ethyl acetate. The organic layer was washedwith water, 5% HCl, 5% sodium bicarbonate and brine solution. The ethylacetate extract was concentrated under reduced pressure and the residuewas purified by silica gel chromatography using 20% acetone-chloroformas the eluent to obtain 90 mgN-(3,5-dichloropyrid-4-yl)-4-methoxy-8-iodo-dibenzo[b,d]furan-1-carboxamideas a white solid, mp: 304° C. (dec).

IR (KBr): 3194, 2924, 2853, 1668, 1627, 1552, 1488, 1389, 1286, 1265,1183, 1107, 893, 808, 778, 658 cm⁻¹.

^(1l H NMR ()300 MHz, DMSO) δ 4.07 (s, 3H), 7.36 (d, 1H, J=8.7 Hz), 7.61(d, 1H, J=8.4 Hz), 7.83 (d, 1H, J=8.7 Hz), 7.92 (d, 1H, J=8.4 Hz), 8.79(s, 2H), 8.81 (s, 1H), 10.86 (s, 1H).

EXAMPLE 46N-(pyrid-4-yl)-4-methoxy-8-iodo-dibenzo[b,d]furan-1-carboxamide

A suspension of intermediate 33 (140 mg, 0.44 mmol) in a mixture ofbenzene (2 ml) and freshly-distilled thionyl chloride (2 ml) was heatedto reflux temperature for 3-4 h The excess thionyl chloride was removedunder vacuum to get the corresponding acid chloride.

To a solution of 4-aminopyridine (100 mg, 0.257 mmol) anddiisopropylethyl amine (52 mg, .515) in dry THF (5 ml) was added asolution of above acid chloride (0.257 mmol) in dry THF (5 ml). Thereaction mixture was stirred at room temperature for 1 h. The reactionmixture was diluted with water (10 ml) and extracted with ethyl acetate(10 ml×3). The ethyl acetate extract was concentrated under reducedpressure and the residue was purified by silica gel chromatography using30% acetone-chloroform as the eluent to obtain 52 mg ofN-(pyrid-4-yl)-methoxy-8-iodo-dibenzo[b,d]furan-1-carboxamide as a whitesolid; mp: 255-257° C.

IR (KBr): 3292, 2929, 1692, 1659, 1582, 1504, 1410, 1330, 1276, 1200,1104, 888, 805, 780, 718 cm⁻¹

¹H NMR (300 MHz, DMSO) δ 4.07 (s,3H), 7.34 (d, 1H, J=8.4 Hz), 7.62 (d,1H, J=8.4), 7.79 (d, 1H, J=4.8), 7.85 (d, 1H, J=4.8 Hz), 7.87 (d, 2H),8.50 (d, 2H, J=5.7 Hz), 8.69 (s, 1H, J=2.1 Hz), 10.86 (s, 1H).

EXAMPLE 47N-(pyrid-3-yl)-4-methoxy-8-iodo-dibenzo[b,d]furan-1-carboxamide

A suspension of intermediate 33 (140 mg, 0.44 mmol) in a mixture ofbenzene (2 ml) and freshly distilled thionyl chloride (2 ml) was heatedto reflux temperature for 3-4 h The excess thionyl chloride was removedunder vacuum to get the corresponding acid chloride.

To a solution of 3-aminopyridine (100 mg, 0.257 mmol) anddiisopropylethylamine (52 mg, 0.515 mmol) in dry THF (3 ml) was added asolution of above acid chloride (0.257 mmol) in dry THF (3 ml). Thereaction mixture was stirred at room temperature for 1 h. The reactionmixture was diluted with water (10 ml) and extracted with ethyl acetate(10 ml×3). The ethyl acetate extract was concentrated under reducedpressure and the residue was purified by silica gel chromatography using20% acetone-chloroform as the eluent to obtain 64 mg ofN-pyrid-3-yl)-methoxy-8-iodo-dibenzo[b,d]furan-1-carboxamide as a whitesolid; mp: 286-287° C.

IR (KBr): 3256, 2930, 1645, 1599, 1524, 1504, 1408, 1333, 1283, 1266,1105, 1019, 884, 795, 705 cm⁻¹

¹H NMR (300 MHz, DMSO) δ 4.07 (s, 3H), 7.34 (d, 1H, J=8.7 Hz), 7.42-7.46(m, 2H), 7.62 (d, 1H, J=8.7), 7.84 (d, 1H, J=8.7 Hz), 8.26 (d, 1H, J=3.9Hz), 8.33 (d, 1H, J=4.8 Hz), 8.72 (s, 1H, J=1.2 Hz), 8.92 (s, 1H, J=2.4Hz), 10.71 (s, 1H).

EXAMPLE 48 N-(4-methylpyrimid-2-yl)-4-methoxydibenzo[b,d]furan-1-carboxamide

A suspension of intermediate 4 (100 mg, 0.00413 mol) in a mixture ofbenzene (2 ml) and freshly distilled thionyl chloride (2 ml) was heatedto reflux temperature for 4 h. The excess thionyl chloride was removedunder vacuum to get the corresponding acid chloride.

To a pre-washed suspension of sodium hydride (82 mg, 2.5 equiv., 2.0mmol, 60% oil dispersion) in DMF (4 ml) was added dropwise a solution of2-amino-4-methyl pyrimidine (108 mg, 0.90 mmol) in DMF (4 ml) at −10° C.A pre-cooled solution of above acid chloride (0.826 mmol) in THF (3 ml)was added, all at once, to the reaction mixture and the contents werestirred at −10° C. for 60 min. The reaction was quenched with brine,diluted with water and extracted with ethyl acetate. The organic layerwas washed with water, 5% HCl, 5% sodium bicarbonate and brine solution.The ethyl acetate extract was concentrated under reduced pressure andthe residue was purified by silica gel chromatography using 15%acetone-chloroform as the eluent to obtain 80 mgN-(4-methylpyrinid-2-yl)-4-methoxy-dibenzo[b,d]furan-1-carboxamide as awhite solid; mp; 272-274° C.

IR (KBr)3246, 2927, 2847, 1693, 1629, 1593, 1510, 1438, 1394, 1269,1175, 1096, 1010, 749 cm⁻¹.

¹H NMR (300 MHz, DMSO) δ 2.49 (s, 3H), 4.05 (s, 3 H), 7.13 (d, 1 H,J=8.4 Hz), 7.25 (d, 1H, J=8.4 Hz), 7.33 (t, 1H), 7.54 (t, 1H), 7.72-7.76(m, 2H), 8.34 (d, 1H, J=7.5 Hz), 8.54 (d, 1H, J=7.5 Hz), 11.05 (s, 1H).

EXAMPLE 49 N-(2,5-dichlorophenyl)-4-methoxydibenzo[b,d]furan-1-carboxamide

A suspension of intermediate 4 (100 mg, 0.00413 mol) in a mixture ofbenzene (2 ml) and freshly distilled thionyl chloride (2 ml) was heatedto reflux temperature for 4 h. The excess thionyl chloride was removedunder vacuum to get the corresponding acid chloride.

To a solution of 2,5-dichloroaniline (117 mg, 0.73 mmol) anddiisopropylethyl amine (157 mg, 1.2 mmol) in dry THF (5 ml) was added asolution of acid chloride (0.61 mmol) in dry THF (5 ml). The reactionmixture was stirred at room temperature for 1 h. The reaction mixturewas diluted with water (10 ml) and extracted with ethyl acetate (10ml×3). The ethyl acetate extract was concentrated under reduced pressureand the residue was purified by silica gel chromatography using 30%ethyl acetate-petroleum ether as the eluent to obtain 40 mg ofN-(2,5-dichlorophenyl)-methoxy-dibenzo[b,d]furan-1-carboxamide as awhite solid; mp: 202° C.

IR (KBr) 3353, 2934, 1665, 1579, 1506, 1452, 1480, 1395, 1280, 1270,1253, 1148, 1090, 1013, 754 cm ⁻¹.

¹H NMR (300 MHz, DMSO) δ 4.07 (s, 3H), 7.29-7.39 (m, 3H), 7.40-7.75 (m,4H), 7.87 (d, 1H, J=7.5 Hz), 8.43 (d, 1H, J=7.5 Hz), 10.27 (s, 1H).

EXAMPLE 50a N-(3,5-dichloropyrid-4-yl)-4-ethoxycarbomethoxydibenzo[b,d]furan-1-carboxamide

A suspension of intermediate 41 (140 mg, 0.44 mmol) in a mixture ofbenzene (2 ml) and freshly distilled thionyl chloride (2 ml) was heatedto reflux temperature for 3-4 h. The excess thionyl chloride was removedunder vacuum to get the corresponding acid chloride.

To a pre-washed suspension of sodium hydride (100 mg, 2.0 equiv., 2.48mmol, 60% oil dispersion) in DMF (5 ml) was added dropwise a solution of3,5-dichloro-4-aminopyridine (200 mg, 1.24 mmol) in DMF (5 ml) at −10°C. A pre-cooled solution of above acid chloride in THF (15 ml) wasadded, all at once, to the reaction mixture and the contents werestirred at −10° C. for 1 h. The reaction was quenched with brine,diluted with water and extracted with ethyl acetate. The organic layerwas washed with water, 5% HCl, 5% sodium bicarbonate and brine solution.The solvent was evaporated and the resulting crude solid was purified bysilica gel column chromatography using 20% ethyl acetate-chloroformprovidedN-(3,5-dichloro-pyrid-4-yl)-4-ethoxycarbomethoxy-dibenzo[b,d]furan-1-carboxamideas a white solid (53a) (30 mg); mp:255-257° C. (dec). IR(KBr) 3183,2924, 1743, 1664, 1548, 1489, 1400, 1297, 1196, 1025, 809, 756 cm⁻¹.

¹H NMR (300 MHz, DMSO) δ 1.23 (t, 3H), 4.22 (q, 2H), 5.16 (s, 2H), 7.30(d, 1H, J=8.4 Hz), 7.36 (t, 1 H, J=8.4 Hz), 7.55 (t, 1H, J=8.4 Hz), 7.77(d, 1H, J=8.4 Hz), 7.84 (d, 1H, J=8.4 Hz), 8.40 (d, 1H, J=8.4 Hz), 8.77(s, 2H), 10.84 (s, 1H)

EXAMPLE 50b N-(3,5-dichloropyrid-4-yl)-4hydroxycarbomethoxydibenzo[b,d]furan-1-carboxamide

A suspension of intermediate 41 (140 mg, 0.44 mmol) in a mixture ofbenzene (2 ml) and freshly distilled thionyl chloride (2 ml) was heatedto reflux temperature for 3-4 h. The excess thionyl chloride was removedunder vacuum to get the corresponding acid chloride.

To a pre-washed suspension of sodium hydride (100 mg, 2.0 equiv., 2.48mmol, 60% oil dispersion) in DMF (5 ml) was added dropwise a solution of3,5-dichloro-4-aminopyridine (200 mg, 1.24 mmol) in DMF (5 ml) at −10°C. A pre-cooled solution of above acid chloride in THF (15 ml) wasadded, all at once, to the reaction mixture and the contents werestirred at −10° C. for 1 h. The reaction was quenched with brine,diluted with water and extracted with ethyl acetate. The organic layerwas washed with water, 5% HCl, 5% sodium bicarbonate and brine solution.The solvent was evaporated and the resulting crude solid was purified bysilica gel column chromatography using 20% ethyl acetate-chloroform toget the desired product as a white solid (53b) (30 mg); mp: 230° C.(dec).

IR (KBr) 3433, 3128, 2890, 1732, 1632, 1487, 1399, 1297, 1193, 1009,830, 723 cm ⁻¹.

¹H NMR (300 MHz, DMSO) δ 5.42 (s, 2H), 7.47 (t, 1 H, J=7.5 Hz), 7.62 (t,1H, J=7.5 Hz), 7.79 (d, 1H, J=8.4 Hz), 7.91 (d, 1H, J=8.4 Hz), 7.95 (d,1H, J=8.4 Hz), 8.22 (d, 1H, J=8.4 Hz), 8.74 (s, 2H), 10.90 (s, 1H).

EXAMPLE 51 N-(3,5-dichloropyrid-4-yl)-4methoxydibenzo[b,d]furan-2-carboxamide

A suspension of intermediate 37 (260 mg, 1.079 mmol) in a mixture ofbenzene (2 ml) and freshly distilled thionyl chloride (2 ml) was heatedto reflux temperature for 3-4 h. The excess thionyl chloride was removedunder vacuum to get the corresponding acid chloride.

To a pre-washed suspension of sodium hydride (107 mg, 2.5 equiv., 2.68mmol, 60% oil dispersion) in DMF (2.5 ml) was added dropwise a solutionof 4-amino-3,5-dichloropyridine (175 mg, 1.074 mmol) in DMF (2.5 ml) at−10° C. A pre-cooled solution of above acid chloride in THF (5 ml) wasadded, all at once, to the reaction mixture and the contents werestirred at −10° C. for 30 min. The reaction was quenched with brine,diluted with water and extracted with ethyl acetate. The organic layerwas washed with water, 5% HCl, 5% sodium bicarbonate and brine solution.Evaporation of solvent and washing of the resulting crude solid withether provided N-(3,5-dichloropyrid-4-yl)-4-methoxydibenzo[b,d]furan-2-carboxamide as a white solid (255 mg); mp: 165-166°C.

IR (KBr) 3252, 3060, 2946, 2848, 1665, 1552, 1485, 1398, 1351, 1197,1099, 812, 749 cm ⁻¹.

¹H NMR (300 MHz, DMSO) δ 4.08 (s, 3 H), 7.46 (t, 1H, J=7.8 Hz), 7.58 (t,1H, J=7.8 Hz), 7.75-7.80 (m, 2H), 8.20 (d, 1H, J=6.9 Hz), 8.43 (s, 1H),8.77 (s, 2H), 10.76 (s, 1H).

EXAMPLE 52 N-(3,5-dichloropyrid-4-yl)-4-methoxydibenzo[b,d]furan-3-carboxamide

A suspension of intermediate 44 (200 mg, 0.826 mol) in a mixture ofbenzene (2 ml) and freshly distilled thionyl chloride (2 ml) was heatedto reflux temperature for 3 h. The excess thionyl chloride was removedunder vacuum to get the corresponding acid chloride.

To a pre-washed suspension of sodium hydride (82 mg, 2.5 equiv., 2.066mmol, 60% oil dispersion) in DMF (2.5 ml) was added dropwise a solutionof 4-amino-3,5-dichloropyridine (134 mg, 0.826 mmol) in DMF (2.5 ml) at−10° C. A pre-cooled solution of above acid chloride (from step 5a) inTHF (10 ml) was added, all at once, to the reaction mixture and thecontents were stirred at −10° C. for 30 min. The reaction was quenchedwith brine, diluted with water and extracted with ethyl acetate. Theorganic layer was washed with water, 5% HCl, 5% sodium bicarbonate andbrine solution. Evaporation of solvent and purification of the resultingcrude solid by silica gel column chromatography using 5% ethylacetate-chloroform provided N-(3,5-dichloropyrid-4-yl)-4-methoxydibenzo[b,d]furan-3-carboxamide as a white solid (230 mg); mp: 176° C.(dec).

IR (KBr) 3301, 2923, 1683, 1629, 1544, 1485, 1315, 1265, 1199, 1095,906, 886, 750, cm ⁻¹.

¹H NMR (300 MHz, DMSO) δ 4.32 (s, 3 H), 7.46 (t, 1H, J=8.4 Hz), 7.58 (t,1H, J=8.4 Hz), 7.76 (d, 1H, J=8.4 Hz ), 7.84 (d, 1H, J=8.4 Hz), 7.95 (d,1 H, J=8.4 Hz), 8.22 (d, 1H, J=8.4 Hz), 8.74 (s, 2H), 10.49 (s, 1H).

EXAMPLE 53 N4-4-methoxy dibenzo[b,d]furan-1-yl)isonicotinamide

Isonicotinic acid (200 mg, 1.62 mmol) and thionyl chloride (5 ml) wasrefluxed for 3 h. The excess thionyl chloride was distilled off and asolution of the resulting solid in dry THF (2.5 ml) was added to asolution of intermediate 39 (345 mg, 1.62 mmol) in THF (5 ml) at roomtemperature. The reaction was stirred at room temperature for 30 min.THF was evaporated, and the residue was partitioned between ethylacetate (20 ml) and water (10 ml). The ethyl acetate extract was washedwith water, concentrated to give 180 mg of crude amide which waspurified by silica gel column chromatography using 20%acetone-chloroform as the eluent to give 80 mg of N4-(4-methoxydibenzo[b,d]furan-1-yl)isonicotinamide as white solid; mp 221° C.

IR (KBr) 3272, 3059, 2838, 1647, 1594, 1522, 1447, 1406, 1296, 1280,1259, 1174, 1100, 745 cm ⁻¹.

¹H NMR (300 MHz, DMSO) δ 4.00 (s, 3 H), 7.20-7.35 (brm, 3H), 7.50 (t,1H, J=7.2 Hz), 7.53-7.71 (m, 2H), 7.71 (d, 2H, J=5.1 Hz), 8.82 (d, 2H,J=5.1 Hz), 10.85 (s, 1H).

EXAMPLE 54 N-(3,5-dichloropyrid-4-yl)-4-methoxydibenzo[b,d]furan-1-sulfonamide

Step 1: 4-methoxy-dibenzo[b,d]furan-1-sulfonyl chloride

Intermediate 40 (400 mg, 1.87 mmol) was dissolved in glacial acetic acid(20 ml) and 17% HCl (10 ml). This solution was cooled to 5° C. and asolution of sodium nitrite (260 mg, 3.74 mmol) in water (5 ml) was addedslowly during 10 min. The reaction was stirred for 1 h at 5° C. Thereaction mixture was then added to a saturated solution of sulfurdioxide (generated from sodium sulfite and conc. HCl) in acetic acid:benzene (3:2) containing cupric chloride dihydrate (100 mg, 0.513 mmol).The reaction was sired at room temperature for 20 h and then pouredwater (500 ml) and extracted with ethyl acetate (3×100 ml). The extractwas washed with water (5×100 ml) and dried over anhydrous sodiumsulfate. The solvent was evaporated to give the product as brown solid(350 mg) which was directly used to make the sulfonamide.

Step 2: N-(3,5-dichloropyrid-4-yl)-4-methoxydibenzo[b,d]furan-1-sulfonamide

To a pre-washed suspension of sodium hydride (33 mg, 2.0 equiv., 0.827mmol, 60% oil dispersion) in DMF (2.5 ml) was added dropwise a solutionof 4-amino-3,5-dichloropyridine (67 mg, 0.413 mmol) in DMF (2.5 ml) at−10° C. A pre-cooled solution of above sulfonyl chloride (from step 1)in THF (10 ml) was added, all at once, to the reaction mixture and thecontents were stirred at −10° C. for 30 min. The reaction was quenchedwith brine, diluted with water and extracted with ethyl acetate. Theorganic layer was washed with water, 5% HCl, 5% sodium bicarbonate andbrine solution. Evaporation of solvent and purification of the resultingcrude solid by silica gel column chromatography using 5% ethylacetate-chloroform provided N-(3,5-dichloropyrid-4-yl)-4-methoxydibenzo[b,d]furan-1-sulfonamide as a dark brown solid (25 mg); mp:242-244° C.

IR (KBr): 2919, 2850, 1628, 1572, 1451, 1392, 1280, 1165, 1097, 952,889, 752 cm⁻¹

¹H NMR (300 MHz, DMSO) δ 4.07 (s, 3H), 7.25-7.32 (m, 2H), 7.55 (t, 1H,J=7.8 Hz), 7.74-7.81 (m, 2H), 8.32 (d, 1H, J=7.8 Hz), 8.52 (s, 2H).

EXAMPLE 55N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-amino-dibenzo[b,d]furan-1-carboxamide

To a suspension of N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-nitrodibenzo[b,d]furan-1-carboxamide (example 38) (4.8 gm, 0.011 mol) inmethanol (25 ml) was added activated raney nickel (1.44 gm, 30% w/w) andstirred at reflux for 10 min. Hydrazine hydrate (1.117 gm, 0.022 mol)was added dropwise to the above refluxing reaction mixture. The reactionwas refluxed for further 30 min. and filtered through celite bed. Thefilterate was concentrated in vaccuo and the residue was purified usingsilica gel chromatography using 15% acetone in chlroform as the eluentto afford 3.5 gm ofN-(3,5-dichloropyrid-4-yl)-4-methoxy-8-amino-dibenzo[b,d]furan-1-carboxamideas white solid. mp: 249° C. (dec).

IR (KBr): 3373, 3300, 2925, 1669, 1605, 1482, 1395, 1281, 1198, 1100,919, 803 cm-1.

¹H NMR (300 MHz, DMSO) δ 4.03 (s, 3H), 5.00 (brs, 2H), 6.79 (d, 1H),7.24 (d, 1H, J=8.1 Hz), 7.39 (d, 1H, J=9.9 Hz), 7.53 (s, 1H), 7.82 (d,1H, J=8.1 Hz), 8.75 (s, 2H), 10.69 (s, 1H).

EXAMPLE 56N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-dibenzo[b,d]furan-1-carboxamide-N-oxide

To a stirred solution ofN-3,5-dichloropyrid-4-yl)-4-difluoromethoxy-dibenzo[b,d]furan-1-carboxamide(example 19) (800 mg, 0.0018 mol) in chloroform (25 ml) was added 50%m-CPBA (1.63 gm, 0.0094 mol) and the reaction mixture was stirred atroom temperature for 48 h The reaction mixture was quenched with 10%aqueous sodium sulfite solution (20 ml) and stirred for 5 minutes. Thelayers were separated and the organic layer was washed with 1N sodiumhydroxide solution (20 ml), water (20 ml) and brine (20 ml). The crudeproduct obtained after evaporation of the solvent was purified by silicagel column chromatography using 30% acetone in chloroform to give 700 mgof the product as white solid, mp ° C.;

IR (KBr): 3218, 3057, 3000, 1659, 1535, 1481, 1452, 1281, 1245, 1219,1195, 1078, 1033, 831, 754 cm ⁻¹.

¹H NMR (300 MHz, DMSO) δ 7.58 (t, J=72 Hz, 1 H), 7.44 (t, 1H), 7.61 (d,1H), 7.64 (t, 1H), 7.84 (d, 1 H), 7.88 (d, 1 H), 8.37 (d, 1 H), 8.80 (s,2H), 10.85 (s, 1 H).

EXAMPLE 57N-(3,5dichloropyrid-4-yl)-4-methoxy-8-cyano-dibenzo[b,d]furan-1-carboxamide

Step 1: 4-methoxy-8-cyano-dibenzo[b,d]furan-1-carboxylic acid

Intermediate 30 (500 mg, 1.99 mmol) was suspended in mixture ofconcentrated hydrochloric acid: water (1:1) (20 ml) and stirred at 50°C. for 30 min. The suspension was cooled to 0° C. and a solution ofsodium nitrite (161 mg, 2.33 mmol) in water (2 ml) was added dropwise in15 min. The reaction was stirred for 30 min. at 0-5° C. and thenneutralized to neutral pH with saturated sodium carbonate solution Thereaction suspension was then added to a pre-cooled solution of CuCN (174mg, 1.99 mmol) and NaCN (238 mg, 4.86 mmol) in water (10 ml). Thereaction was allowed to come to room temperature for 2 h. The reactionmixture was then poured into water (100 ml) and the solid was filteredand then purified by column chromatography using 15% ethylacetate-chloroform as the eluent to obtain 250 mg of the product aswhite solid.

¹H NMR (300 MHz, DMSO) δ 4.08 (s, 3H), 6.87 (d, 1H), 7.41 (d, 1H, J=6.9Hz), 8.00-8.12 (m, 2H), 9.29 (s, 1H), 12.25 (brs, 1H).

Step 2:N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-cyano-dibenzo[b,d]furan-1-carboxamide

A suspension of 4-methoxy-8-cyano-dibenzo[b,d]furan-1-carboxylic acid(80 mg, 0.299 mmol) (from above step) in a mixture of benzene (2 ml) andfreshly distilled thionyl chloride (2 ml) was heated to refluxtemperature for 3-4 h. The excess thionyl chloride was removed undervacuum to get the corresponding acid chloride which was subjected thenext reaction as such.

To a pre-washed suspension of sodium hydride (29 mg, 2.5 equiv., 0.749mmol, 60% oil dispersion) in DMF (3 ml) was added dropwise a solution of4-amino-3,5-dichloropyridine (51 mg, 0.314 mmol) in DMF (2 ml) at −10°C. A pre-cooled solution of above acid chloride (from step 3a) in THF (3ml) was added, all at once, to the reaction mixture and the contentswere stirred at −10° C. for 30 min The reaction was quenched with brine,diluted with water and extracted with ethyl acetate. The organic layerwas washed with water, 5% HCl, 5% sodium bicarbonate and brine solution.The solvent was evaporated to afford a crude solid was purified bycolumn chromatography using 10% ethyl acetate-chloroform as the eluentto obtain 60 mg ofN-(3,5-dichloropyrid-4-yl)-4-methoxy-8-chloro-dibenzo[b,d]furan-1-carboxamideas a white solid; mp: >250° C.

IR (KBr): 3183, 3025, 2921, 2226, 1654, 1553, 1488, 1396, 1289, 1185,1096, 1020, 808 cm⁻¹

¹H NMR (300 MHz, DMSO) δ 4.11 (s, 3H), 7.50 (d, 1H, J=8.4 Hz), 8.04-8.09(m, 3H), 8.83 (s, 2H), 8.89 (s, 1H ), 10.96 (s, 1H).

EXAMPLE 58N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-nitro-dibenzo[b,d]furan-1-carboxamide

A solution of intermediate 51 (100 mg, 0.30 mmol) (from step 7) in amixture of benzene (2 ml) and freshly distilled thionyl chloride (2 ml)was heated to reflux temperature for 4 h. The excess thionyl chloridewas removed under vacuum to get the corresponding acid chloride

To a pre-washed suspension of sodium hydride (25 mg, 60% oil dispersion)in DMF (3 ml) was added dropwise a solution of4-amino-3,5-dichloropyridine (53 mg, 0.30 mmol) in DMF (2 ml) at −10° C.A pre-cooled solution of above acid chloride (0.30 mmol) in THF (5 ml)was added, all at once, to the reaction mixture and the contents werestirred at −10° C. for 30 min. The reaction was quenched with brine,diluted with water and filtered to give a crude solid which was purifiedby silica gel chromatography using 10% acetone in chloroform as theeluent to provide 100 mg ofN-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-nitro-dibenzo[b,d]furan-1-carboxamideas white solid. mp: >270° C.

IR (KBr): 3213, 2926, 1664, 1555, 1526, 1488, 1339, 1285, 1199, 1090,904, 823 cm-1.

¹H NMR (300 MHz, DMSO) δ 7.63 (t, 1H, J=72 Hz), 7.77 (d, 1H), 8.09 (d,1H), 8.13 (d, 1H), 8.52 (dd, 1H, J=9.3 Hz, 2.4 Hz), 8.86 (s, 2H), 9.39(d, 1H, J=2.7 Hz), 11.21 (s, 1H).

EXAMPLE 59N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-amino-dibenzo[b,d]furan-1-carboxamide

A mixture ofN-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-nitro-dibenzo[b,d]furan-1-carboxamide(example 58) (100 mg), methanol (10 ml) and 10% Pd/C (10 mg) washydrogenated at 60 psi for 12 h. Filteration of the reaction mixtureover celite bed and removal of solvent methanol under reduced pressureaffordedN-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-amino-dibenzo[b,d]furan-1-carboxamideas white solid. mp: >270° C.

IR (KBr): 3436, 3360, 3185, 2921, 1659, 1555, 1484, 1391, 1292, 1195,1133, 1055, 910, 811, 674 cm-1.

¹H NMR (300 MHz, DMSO) δ 5.14 (brs, 2H), 6.86 (dd, 1H, J=8.7 Hz, 2.4Hz), 7.53 (t, 1H, J=72 Hz), 7.46-7.51 (m, 2H), 7.80 (d, 1H, J=9.0 Hz),8.80 (s, 2H), 10.96 (s, 1H).

EXAMPLE 603,5-Dichloro-4-(4-ethoxydibenzo[b,d]furan-1-ylcarboxamido)pyridine

To a stirred and cooled (−10° C.) suspension of 60% sodium hydride (58mg, 1.4 mmol) in DMF (3 ml) was added 3,5-dichloro-4-aminopyridine (120mg, 0.70 mmol) and the mixture was stirred for 30 min. The acidchloride, prepared from intermediate 58(150 mg 0.58 mmol) in THF (5 ml)was added to the reaction mixture in one portion and the mixture wasfurther stirred at the same temperature for 30 min. The reaction mixturewas quenched with ice-cold water (25 ml) and extracted with ethylacetate (3×20 ml). The combined organic extracts were washed with 1N HCl(20 ml), water (20 ml), brine (20 ml) and dried (Na₂SO₄). The crudeproduct obtained after evaporation of the solvent was purified by silicagel column chromatography using 50% ethyl acetate in petroleum ether togive 85 mg (36%) of the product as white solid, mp 289-292° C.; IR (KBr)3207, 2928, 1665, 1488, 1281 cm ⁻¹. ¹H NMR (300 MHz, CDCl₃) δ 1.61 (t,J=6.9 Hz, 3 H), 4.38 (q, J=6.9 Hz, 2 H), 7.02 (d, J=8.7 Hz, 1 H), 7.30(t, J=8.2 Hz, 1 H), 7.49 (t, J=8.2 Hz, 1 H), 7.62 (s, 1 H), 7.66 (d,J=8.2 Hz, 1 H), 7.76 (d, J=8.7 Hz, 1 H), 8.50 (d, J=8.2 Hz, 1 H), 8.58(s, 2H).

EXAMPLE 61 N1-Benzyl-4-cyclopentyloxydibenzo[b,d]furan-1-carboxamide

To a stirred solution of benzylamine (30 mg, 0.27 mmol) andtriethylamine (0.5 g, 4.9 mmol) in dry dichloromethane (5 ml) was addedthe acid chloride, prepared from intermediate 60 (40 mg 0.135 mmol) indichloromethane (5 ml) and the mixture was stirred at room temperaturefor 30 min. The reaction mixture was quenched with ice-cold water (25ml) and extracted with dichloromethane (2×20 ml). The combined organicextracts were washed with 1N HCl (20 ml), water (20 ml), brine (20 ml)and dried (Na₂SO₄). The crude product obtained after evaporation of thesolvent was purified by silica gel column chromatography using 25% ethylacetate in petroleum ether to give 15 mg (29%) of the product as whitesolid, mp 172-175° C.; IR (KBr) 3286, 2958, 2869, 1641, 1537, 1293, 1275cm ⁻¹, ¹H NMR (300 MHz, CDCl₃) δ 1.59-1.70 (m, 2 H), 1.89-1.94 (m, 2 H),2.00-2.04 (m, 4 H), 4.75 (d, J=6.3 Hz, 2 H), 5.05 (quint., J=4.5 Hz, 1H), 6.33 (brs, 1 H), 6.93 (d, J=8.4 Hz, 1 H), 7.26-7.49 (m, 7 H), 7.62(d, J=8.1 Hz, 1 H), 8.40 (d, J=7.5 Hz, 1 H).

EXAMPLE 62 4-(4-Cyclopentyloxydibenzo[b,d]furan-1-ylcarboxamido)pyridine

To a stirred solution of 4-aminopyridine (30 mg, 0.32 mmol) andtriethylamine (0.5 g, 4.9 mmol) in dry THF (5 ml) was added the acidchloride, prepared from intermediate 60 (50 mg 0.16 mmol) in dry THF (5ml) and the mixture was stirred at room temperature for 30 min. Thereaction mixture was quenched with ice-cold water (25 ml) and extractedwith ethyl acetate (2×20 ml). The combined organic extracts were washedwith 1N HCl (20 ml), water (20 ml), brine (20 ml) and dried Na₂SO₄). Thecrude product obtained after evaporation of the solvent was purified bysilica gel column chromatography using 35% ethyl acetate in petroleumether to give 23 mg (37%) of the product as white solid, mp 250-253° C.;IR (KBr) 3291, 2964, 2870, 1655, 1586, 1507, 1278 cm ⁻¹. ¹H NMR (300MHz, CDCl₃) δ 1.68-1.79 (m, 2 H), 1.89-1.94 (m, 2 H), 2.02-2.06 (m, 4H), 5.09 (quint., J=4.5 Hz, 1 H), 6.99 (d, J=8.4 Hz, 1 H), 7.33 (t,J=8.1 Hz, 1 H), 7.50 (t, J=7.3 Hz, 1 H), 7.59 (d, J=8.4 Hz, 1 H),7.63-7.67 (m, 4 H), 7.98 (s, 1 H), 8.33 (d, J=7.4 Hz, 1 H), 8.57 (d,J=8.4 Hz, 1H).

EXAMPLE 633,5-Dichloro-4-(4-cyclopentyloxydibenzo[b,d]furan-1-ylcarboxamido)pyridine

To a stirred and cooled (−10° C.) suspension of 60% sodium hydride (50mg, 1.4 mmol) in DMF (3 ml) was added 3,5-4chloro-4-aminopyridine (100mg, 0.70 mmol) and the mixture was stirred for 30 min. The acidchloride, prepared from intermediate 60(150 mg, 0.50 mmol) in THF (5 ml)was added to the reaction mixture in one portion and the mixture wasfurther stirred at the same temperature for 30 min. The reaction mixturewas quenched with ice-cold water (25 ml) and extracted with ethylacetate (3×20 ml). The combined organic extracts were washed with 1N HCl(20 ml), water (20 ml), brine (20 ml) and dried (Na₂SO₄). The crudeproduct was obtained after evaporation of the solvent as white solid 90mg (40%/), mp 284-286° C.;

IR (KBr) 3191, 2953, 1659, 1487, 1277 cm ⁻¹;

¹H NMR (300 MHz, CDCl₃) δ 1.70-1.77 (m, 2 H), 1.92-2.00 (m, 2 H),2.05-2.11 (m, 4 H), 5.13 (quint., J=4.5 Hz, 1 H), 7.04 (d, J=8.7 Hz, 1H), 7.32 (t, J=8.5 Hz, 1 H), 7.50 (t, J=8.5 Hz, 1 H), 7.65 (d, J=8.7 Hz,1 H), 7.69 (s, 1 H), 7.78 (d, J=8.7 Hz, 1 H), 8.53 (d, J=8.7 Hz, 1 H),8.60 (s, 2 H).

EXAMPLE 64 4-(4-Methylsulfanyldibenzo[b,d]furan-1-ylcarboxamido)pyridine

A mixture of intermediate 61 (100 mg, 0.38 mmol),dicyclohexylcarbodimide (88 mg, 0.42 mmol), and dimethylaminopyridine (4mg, 0.03 mmol) in THF (5 ml) was stirred at room temperature for 5 min.A solution of 4-aminopyridine (40 mg, 0.42 mmol) in THF (2 ml) was addedand the mixture stirred at room temperature for 3 h. The mixture wasfiltered to remove DCU and the filterate was diluted with ethyl acetate(50 ml) and washed with water (3×50 ml), brine (50 ml) and dried(Na₂SO₄). The crude product obtained after evaporation of the solventwas purified by silica gel column chromatography using 3% methanol inchloroform to give 30 mg (23%) of the product as white solid, mp242-245° C.;

IR (KBr) 3273, 3063, 2925, 1640, 1537, 1445, 1197 cm ⁻¹.

¹H NMR (300 MHz, DMSO-d₆) δ 3.02 (s, 3 H), 7.44 (t, J=7.8 Hz, 1 H, 7.65(t, J=7.8 Hz, 1 H), 7.83-7.87 (m, 3 H), 7.97 (dd, J=8.2, 2.1 Hz, 2 H),8.17 (d, J=7.5 Hz, 1 H), 8.54 (brs, 2 H, 11.22 (s, 1 H).

EXAMPLE 65 N3-(4-Methoxydibenzo[b,d]furan-1-yl)nicotinamide

To a stirred and cooled (0° C.) solution of intermediate 40 (100 mg,0.47 mmol) and triethylamine (95 mg, 0.94 mmol), in dry dichloromethane(10 ml) was added nicotinoyl chloride hydrochloride (80 mg, 0.56 mmol)in dry dichloromethane (5 ml). The cooling bath was removed and thereaction mixture was stirred at room temperature for 12 h. The solventwas removed under reduced pressure and the residue was diluted withEtOAc (30 ml). The EtOAc solution was washed with water (30 ml), brine(20 ml) and dried (Na₂SO₄). The crude product obtained after evaporationof the solvent was purified by silica gel column chromatography using 1%methanol in chloroform to give 35 mg (21%) of the product as off-whitesolid, mp 200-203° C.;

IR (KBr) 3247, 1636, 1523, 1278, 1101 cm ⁻¹;

¹H NMR (300 Mz, CDCl₃) δ 4.06 (s, 3 H), 6.97 (d, J=8.7 Hz, 1 H), 7.29(t, J=7.2 Hz, 1 H), 7.45 (t, J=7.2 Hz, 1 H), 7.48 (d, J=8.7 Hz, 1 H),7.57 (d, J=7.2 Hz, 1 H), 7.62 (d, J=8.1 Hz, 1 H, 7.71 (d, J=7.2 Hz, 1H), 8.30 (brs, 2 H), 8.81 (s, 1H), 9.24 (s, 1 H).

EXAMPLE 66 N1-Benzyl-4-methoxydibenzo[b,d]furan-1-sulfonamide

A solution of intermediate 38 (200 mg, 1.08 mmol) in dry chloroform (5ml) was added in one portion to a stirred and cooled (0° C.) solution ofchlorosulfonic acid (118 mg, 1.08 mmol) in dry chloroform (5 ml). Thereaction mixture was allowed to warm to room temperature over a periodof 1 h. The solvent was evaporated under reduced pressure to give crude4-methoxydibenzo[b,d]furan-1-sulfonyl chloride;

To a stirred solution of benzylamine (75 mg, 0.68 mmol) andtriethylamine (0.3 g, 2.9 mmol) in dry THF (5 ml) was added the abovesulfonyl chloride (100 mg) in dry THF (5 ml) and the mixture was stirredat room temperature for 30 min. The reaction mixture was quenched withice-cold water (25 ml) and extracted with ethyl acetate (2×20 ml). Thecombined organic extracts were washed with 1N HCl (20 ml), water (20ml), brine (20 ml) and dried (Na₂SO₄). The crude product obtained afterevaporation of the solvent was purified by silica gel columnchromatography using 50% ethyl acetate in petroleum ether to give 30 mg(38%) of the product as white solid, mp 180-185° C.;

IR (KBr) 3306, 2929, 2845, 1599, 1573, 1391, 1279, 1159 cm ⁻¹;

¹H NMR (300 MHz, CDCl₃) δ 4.06 (d, J=6.3 Hz, 2 H), 4.13 (s, 3 H), 4.91(t, J=6.3 Hz, 1 H), 6.99-7.02 (m, 3 H), 7.08-7.14 (m, 3 H), 7.40 (t,J=6.9 Hz, 1 H), 7.56 (t, J=6.9 Hz, 1 H), 7.68 (d, J=8.7 Hz, 1 H), 7.95(d, 8.7 Hz, 1 H), 8.54 (d, J=7.5 Hz, 1H).

EXAMPLE 67 4-(4-Methoxydibenzo[b,d]furan-1-ylsulfonamido)pyridine

A solution of intermediate 38 (200 mg, 1.08 mmol) in dry chloroform (5ml) was added in one portion to a stirred and cooled (0° C.) solution ofchlorosulfonic acid (118 mg, 1.08 mmol) in dry chloroform (5 ml). Thereaction mixture was allowed to warm to room temperature over a periodof 1 h. The solvent was evaporated under reduced pressure to give crude4-methoxydibenzo[b,d]furan-1-sulfonyl chloride;

Reaction of 4-aminopyridine (65 mg, 0.70 mmol) with crude4-methoxydibenzo[b,d]-furan-1-sulfonyl chloride (100 mg) in presence oftriethylamine (0.3 g, 2.9 mmol) as described in Example 8 followed bysilica gel column chromatography using 10% MeOH in chloroform gave 30 mg(25%) of the product as white solid; IR (KBr) 2920, 2850, 1634, 1481,1344, 1111, 1093 cm ⁻¹; ¹H NMR (300 MHz, DMSO-d₆) δ 4.02 (s, 3 H), 6.83(d, J=7.5 Hz, 2 H), 7.24 (d, J=8.7 Hz, 1 H), 7.39 (t, J=7.2 Hz, 1 H),7.53 (t, J=6.9 Hz, 1 H), 7.70 (d, J=8.4 Hz, 1 H), 7.87-7.90 (m, 3 H),8.83 (d, J=7.8 Hz, 1 H), 12.7 (brs, 1 H).

EXAMPLE 683,5-Dichloro-4-(4-ethoxydibenzo[b,d]furan-1-ylcarboxamido)pyridine-N-oxide

To a stirred solution of3,5-dichloro-4-(4-ethoxydibenzo[b,d]furan-1-ylcarboxamido)-pyridine(example 60) (40 mg, 0.099 mmol) in chloroform (20 ml) was added 50%m-CPBA (100 mg, 0.29 mmol) and the reaction mixture was refluxed withstirring for 2.5 h. The reaction mixture was quenched with 10% aqueoussodium sulfite solution (20 ml) and stirred for 5 minutes. The layerswere separated and the organic layer was washed with 1N sodium hydroxidesolution (20 ml), water (20 ml) and brine (20 ml). The crude productobtained after evaporation of the solvent was purified by silica gelcolumn chromatography using 5% methanol in chloroform to give 20 mg(48%) of the product as white solid, mp 265-267° C.;

IR (KBr) 3216, 2924, 2854, 1657, 1475, 1280, 1098 cm ⁻¹;

¹H NMR (300 MHz, CDCl₃) δ 1.61 (t, J=6.9 Hz, 3 H), 4.38 (q, J=6.9 Hz, 2H), 7.01 (d, J=8.4 Hz, 1 H), 7.32 (t, J=8.2 Hz, 1 H), 7.50 (t, J=8.2 Hz,1 H), 7.59 (brs, 1 H), 7.64 (d, J=8.4 Hz, 1 H), 7.72 (d, J=8.4 Hz, 1 H),8.26 (s, 2 H), 8.48 (d, J=8.4 Hz, 1 H).

EXAMPLE 693,5-Dichloro-4-(4-cyclopentyloxydibenzo[b,d]furan-1-ylcarboxamido)pyridine-N-oxide

To a stirred solution of3,5-dichloro-4-(4-cyclopentyloxydibenzo[b,d]furan-1-ylcarboxamido)-pyridine(example 63) (50 mg, 0.113 mmol) in chloroform (20 ml) was added 50%m-CPBA (110 mg, 0.34 mmol) and the reaction mixture was refluxed withstirring for 2.5 h. The reaction mixture was quenched with 10% aqueoussodium sulfite solution (20 ml) and stirred for 5 minutes. The layerswere separated and the organic layer was washed with 1N sodium hydroxidesolution (20 ml), water (20 ml) and brine (20 ml). The crude productobtained after evaporation of the solvent gave 25 mg (48%) of theproduct as white solid; mp 255-258° C.;

IR (KBr) 3212, 3185, 2923, 2852, 1657, 1474, 1281, 1242, 1100 cm ⁻¹;

¹H NMR (300 MHz, CDCl₃) δ 1.71-1.77 (m, 2 H), 1.90-2.02 (m, 2 H),2.03-2.12 (m, 4 H), 5.11 (quint, J=4.5 Hz, 1 H), 7.00 (d, J=8.7 Hz, 1H), 7.31 (t, J=8.5 Hz, 1 H), 7.49 (t, J=8.5 Hz, 1 H), 7.60 (s, 1 H),7.63 (d, J=7.8 Hz, 1 H), 7.72 (d, J=8.4 Hz, 1 H), 8.26 (s, 2 H), 8.48(d, J=8.7 Hz, 1 H).

EXAMPLE 70N-Formyl-1-methoxy-4-[4-methoxyphenylaminosulphonyl]-9H-carbazole

Intermediate 63 (0.2 g, 0.62 mM) was dissolved in 40 ml of chloroform.To it was added p-anisidine (0.21 g, 1.66 mM), 0.19 g triethylamine andthe reaction was refluxed for 18 hrs. Solvent was evaporated and theresidue was extracted in ethyl acetate. The organic layer was washedwith 10% HCl solution, brine and then dried over anhydrous Na₂SO₄. Itwas then evaporated to obtain the crude residue which was then purifiedover silica gel column using ethylacetate-hexane system to obtain thedesired compound as beige solid with a yield of 65% (0.16 g); mp190-192° C.

¹H NMR (d₆-DMSO, 300 MHz) δ 3.62 (3H, s), 4.08 (3H, s), 6.72-6.91 (4H,m), 7.35 (1H, d, J=8.7 Hz), 7.51 (1H, d of t, J=8.1 Hz, J=1.2 Hz), 7.65(1H, d of t, J=8.1 Hz, J=1.2 Hz), 7.85 (1H, d, J=8.4 Hz), 8.66 (1H, d,J=8.1 Hz), 8.83 (1H, d, J=7.8 Hz), 10.26 (1H, s), 10.35 (1H, br s).

IR (KBr): 1708, 1574, 1509, 1454, 1393, 1312, 1275, 1167, 1136, 1011cm⁻¹.

EXAMPLE 71 1-methoxy-4-[4-methoxyphenylaminosulphonyl]-9H-carbazole

N-Formyl-1-methoxy-4-[4-methoxyphenylaminosulphonyl]-9H-carbazole(example 70) (0.1 g, 0.24 mM) was dissolved in 18 mL of 20% aqueous THFsolution. The reaction mixture was cooled to 0° C. in an ice bath. To itwas added NaBH₄ (0.055 g, 1.45 mM) portion wise. The reaction mixturewas stirred overnight Solvent was evaporated and the aqueous layer wasextracted with EtOAc. The organic layer was washed with brine and driedover anh. Na₂SO₄. It was filtered and concentrated to yield the crudeproduct. The crude product was purified over a silica gel column usingEtOAc- hexane as a solvent system to yield the desired compound as awhite semi-solid with a yield of 66% (0.062 g).

¹H NMR (d₆-DMSO, 300 MHz) 3.60 (3H, s), 4.04 (3H, s), 6.69 (2H, d, J=9Hz), 6.85 (2H, d, J=9 Hz), 7.06 (1H, d, J=8.4 Hz), 7.19 (1H, d of t,J=6.9 Hz, J=1.2 Hz), 7.44 (1H, d of t, J=8.1 Hz, J=1.2 Hz), 7.54 (1H, d,J=8.1 Hz), 7.62 (1H, d, J=8.4 Hz), 8.71 (1H, d, J=8.1 Hz), 10.05 (1H,s), 11.85 (1H, s).

IR (KBr): 3342, 2925, 1624, 1566, 1508, 1458, 1402, 1324, 1290, 1153,1128, 1100, 1011, 963, 804, 753, 672 cm⁻¹.

EXAMPLE 72N-Formyl-1-methoxy-4-[4-methylphenylaminosulphonyl]-9H-carbazole

Intermediate 63 (0.2g, 0.62 mM) was dissolved in 50 ml of chloroform. Toit was added p-toludine (0.165 g, 1.54 mM) and 0.16 g triethylamine. Thereaction was refluxed for 15 hrs. Solvent was evaporated and the residuewas taken up in ethyl acetate. The organic layer was washed with 10% HClsolution, brine and then dried over anh Na₂SO₄. It was then evaporatedto obtain the crude residue which was then purified over silica gelcolumn using ethylacetate-hexane system to obtain the desired compoundas beige solid with a yield of 75% (0.18 g); mp 193-199° C.

¹H NMR (d₆-DMSO, 300 MHz) 2.19 (3H, s), 4.13 (3H, s), 6.9-7.04 (4H, m),7.42 (1H, d, J=8.7 Hz), 7.57 (1H, t, J=8.4 Hz), 7.7 (1H, t, J=8.4 Hz),7.94 (1H, d, J=8.7 Hz), 8.70 (1H, d, J=7.8 Hz), 8.89 (1H, d, J=7.8 Hz),10.3 (1H, s), 10.63 (1H, s).

IR (KBr): 3258, 1706, 1572, 1511, 1451, 1393, 1305, 1273, 1078, 1009,806 cm⁻¹.

EXAMPLE 73 1-methoxy-4-[4-methylphenylaminosulphonyl]-9H-carbazole

N-Formyl-1-methoxy-4-[4-methylphenylaminosulphonyl]-9H-carbazole(example 72) (0.14 g, 0.35 mM) was dissolved in 15 mL of 20% aqueous THFsolution. The reaction mixture was cooled to 0° C. in an ice bath. To itwas added NaBH₄ (0.08 g, 2.1 mM) portion wise. The reaction mixture wasstirred for 4-5 hrs. Solvent was evaporated and the aqueous layer wasextracted with EtOAc. The organic layer was washed with brine and driedover anh. Na₂SO₄. It was filtered and concentrated to yield the desiredcompound as a white solid with a yield of 99% (0.13 g). mp 199-203° C.

¹H NMR (d₆-DMSO, 300 MHz) δ 2.11 (3H, s), 4.04 (3H, s), 6.8-6.93 (4H,m), 7.07 (1H, d, J=8.4 Hz), 7.2 (1H, t, J=7.8 Hz), 7.44 (1H, t, J=6.6Hz), 7.53 (1H, d, J=8.4 Hz), 7.67 (1H, d, J=8.4 Hz), 8.71 (1H, d, J=8.4Hz), 10.28 (1H, s), 11.86 (1H, s).

IR (KBr): 3393, 1562, 1512, 1322, 1290, 1150, 1100, 813 cm⁻¹.

EXAMPLE 741-methoxy-4-[4-methylphenylaminosulphonyl-N′′-methyl]-9H-carbazole

In a 50 ml round bottomed flask was taken1-methoxy-4-[4-methyl-phenylaminosulphonyl]-9H-carbazole (example 73)(0.095 g, 0.26 mM) dissolved in 10 ml of acetone. To it was added 0.071g of K₂CO₃ and methyl iodide (0.146 g, 1.03 mM). The reaction mixturewas stirred at room temperature for 4 hrs. The reaction mixture wasfiltered and the filtrate was concentrated and the obtained residue waspurified on a silica gel column. The desired compound was obtained as awhite solid with a yield of 76% (0.074 g). mp 184-189° C.

¹H NMR (d₆-DMSO, 300 Mz) δ 2.2 (3H, s), 3.13 (1H, s), 4.07 (3H, s),6.93-7.02 (5H, m), 7.09 (1H, d, J=8.4 Hz), 7.38 (1H, t, J=7.2 Hz), 7.50(2H, d, J=8.1 Hz), 8.29 (1H, d, J=8.1 Hz), 11.88 (1H, s).

IR (KBr): 3350, 2925, 1627, 1563, 1446, 1338, 1269, 1146, 1100, 681, 573cm⁻¹.

EXAMPLE 75 1-methoxy-4-[4-methylphenylaminosulphonyl-N′-methyl]-9methylcarbazole

In a 100 ml round bottomed flask was taken 5.2 mg NaH. It was washedwith pet ether and to it was added dry THF. The flask was cooled in anice bath and to it was added a solution of1-methoxy-4-[4-methylphenylaminosulphonyl-N′-methyl]-9H-carbazole.(example 73) (0.042 g, 0.1 mM) in dry THF. The reaction mixture wasstirred for 1 hr and methyl iodide (0.031 g, 0.22 mM) was added. Thereaction was stirred further for 48 hrs at room temperature. Reactionmixture was quenched with water and extracted with ethyl acetate. Theorganic layer was washed with water and brine and dried over anh.Na₂SO₄. It was then evaporated to obtain the desired compound as a whitesolid with a yield of 68% (0.029 g); mp 174-180° C.

¹H NMR (d₆-DMSO, 300 MHz) δ 2.21 (3H, s), 3.15 (1H, s), 4.04 (3H, s),4.19 (3H, s), 6.96-7.14 (6H, m), 7.45-7.64 (3H, m), 8.4 (1H, d, J=7.8Hz).

IR (KBr): 2922, 1563, 1508, 1473, 1298, 1268, 1164, 1110, 935, 871, 747cm⁻¹.

EXAMPLE 76 1-methoxy-4-[4-pyridinylaminosulphonyl]-9H-carbazole

Intermediate 63 (0.2 g, 0.62 mM) was dissolved in 5 ml of pyridine. Toit was added 4-aminopyridine (0.35 g, 3.7 mM) and the reaction mixturewas heated at 100° C. for three hours. The solvent was evaporated andthe residue was purified on a silica gel column using MeOH(CHCl3 toobtain the deformylated desired compound as a white solid with a yieldof 41% (0.097 g); mp 311-313° C.

¹H NMR (d₆-DMSO, 300 MHz) δ 4.03 (3H, s), 6.8 (2H, d, J=6.3 Hz), 7.05(1H, d, J=8.1 Hz), 7.11 (1H, t, J=7.8 Hz), 7.36 (1H, t, J=7.5 Hz), 7.46(1H, d, J=7.8 Hz), 7.72-7.9 (3H, m), 8.90 (1H, br s), 11.62 (1H, br s).

IR (KBr): 3452, 2612, 1624, 1568, 1493, 1479, 1342, 1287, 1194, 1114,960, 933, 778 cm⁻¹.

EXAMPLE 77 N4-(2,6-Dichlorophenyl)-1-methoxy-9H-4-carbazolsulphonamide

A solution of 4-amino-3,5-dichloropyridine (0.3 g, 1.85 mM) in dry THFwas added dropwise to a stirred solution of EtMgBr (1 eq, freshlyprepared). To this solution was added intermediate 63 (0.2 g, 0.62 mM)in THF at room temperature. The reaction mixture was refluxed for 18hrs. The reaction was quenched with aq. NH₄Cl and after the standardworkup the residue was purified using column chromatography to obtainthe desired product as a beige solid with a yield of 15% (0.04 g). mp201-205° C.

¹H NMR (d₆-DMSO, 300 MHz) δ 4.07 (3H, s), 7.03-7.09 (2H, m), 7.2-7.26(1H, m), 7.35-7.42 (3H, m), 7.5-7.58 (2H, m), 8.55 (1H, d, J=8.1 Hz),9.9 (1H, s), 11.79 (1H, s).

IR (KBr): 3377, 3276, 1627, 1611, 1564, 1444, 1403, 1369, 1322, 1292,1268, 1156, 1131, 1100, 1014, 957, 884, 785, 675 cm⁻¹. MS Obsd & Calcd[M+NH₄]438.

EXAMPLE 78N4-(2,6-Dichlorophenyl)-9-formyl-1-methoxy-9H-4-carbazolsulphonamide

A solution of 4-amino-3,5-dichloropyridine (0.45 g, 2.77 mM) in dry THFwas added dropwise to a stirred solution of EtMgBr (1 eq, freshlyprepared). To this solution was added intermediate 63 (0.3 g, 0.924 mM)in THF at room temperature. The reaction mixture was stirred for 18 hrsat room temperature. The reaction was quenched with aq. NH₄Cl and afterthe standard workup the residue was purified using column chromatographyto obtain the desired product as a beige semi-solid with a yield of 9%(0.04 g).

¹H NMR (d₆-DMSO, 300 MHz) δ 4.12 (3H, s), 6.90 (1H, t, J=7.2 Hz), 7.22(1H, d, J=9 Hz), 7.34-7.45 (4H, m), 7.52 (1H, d, J=8.1 Hz), 7.86 (1H, d,J=8.4 Hz), 8.03 (1H, d, J=8.1 Hz), 9.48 (1H, s), 12.05(1H, s).

IR (KBr): 1697, 1606, 1573, 1509, 1453, 1393, 1308, 1273, 1167, 1134,1011,984 cm⁻¹.

MS Obsd & Calcd [M-H] 447.

EXAMPLE 79 N4-(4-pyridyl)-1-methoxy-9H-4-carbazole carboxamide

To a stirred solution of intermediate 72 (0.1 gm, 0.4145 mmoles) in dryDMF (5 ml) at room temperature, 4-aminopyridine (0.043 gm, 0.456 moles)was added followed by N-ethyl N′-diethylaminopropyl carbodiimide HCl(0.104 gm, 0.539 mmoles) and DMAP (5.0 mg, 0.04 mmoles).To the abovesolution triethylamine (0.08 ml, 0.58 mmoles) was added and the reactionmixture was stirred at the same temperature for 15 hours. The reactionmixture was poured in to water (20 ml) and extracted with ethyl acetate(2×20 ml). The organic layer was washed with water (3×20 ml) followed bybrine (15 ml), dried over Na₂SO₄ and concentrated to give 0.1 gm ofcrude material which was purified by column chromatography, to give 20mg of the title compound as pale yellow solid, m. p: >250° C.

IR (KBr, cm⁻¹): 3413, 2931, 1710, 1662, 1601, 1507, 1414, 1325, 1288,1178, 1099, 1011 and 700.

¹H NMR (300 MHz, DMSO-d₆, δ): 4.1(s, 3H), 7.1 (d, J=8.1 Hz, 2H), 7.4 (t,J=7.5 Hz, 1H), 7.5 (d, J=8.1 Hz, 2H), 8.0 (b s, 2H), 8.2 (d, J=8.4 Hz,1H), 8.6 (b s, 2H),11.2 (s, 1H), 11.7 (s, 1H).

EXAMPLE 80 N4-(3,5-dichloro-4-pridyl)-1-methoxy-9H-4-carbazolecarboxamide

To a solution of intermediate 72 (202 mg, 0.838 mmoles) in dry DMF (5ml), carbonyldiimidazole (136 mg, 0.838 mmoles) was introduced at 25°C., under nitrogen atmosphere. The reaction mixture was stirred for 4hrs. In another two neck round bottom flask 60% sodium hydride (84 mg,2.095 mmoles) was added to a solution of 3,5 dichloro-4-aminopyridine(136.62 mg, 0.838 mmoles) in dry DMF (3 ml), at −10° C. andstirred for 1 hr, under nitrogen atmosphere. To this solution a solutionof starting material-imidazole complex in dry DMF was added at −10°C.The reaction mixture was stirred at −10° C. for 30 min and at 25° C.for 48 hrs under nitrogen atmosphere. To the reaction mixture water (5ml) was added and neutralized with 1N HCl. The solid precipitated wasfiltered to yield 20 mg of the title compound as pale brown coloredsolid, m. p: >250° C.

IR (KBr, cm⁻¹): 668, 730, 745, 1014, 1102, 1232, 1268, 1283, 1307, 1402,1462, 1480, 1546, 1561, 1573, 1660, 2938 and 3185.

¹H NMR (300 MHz, DMSO-d₆, δ): 4.070(s, 3H), 7.040-7.127(m, 2H),7.340-7.389(t, J=7.35 Hz, 1H), 7.489-7.516(d, J=8.1 Hz,1H),7.621-7.647(d, J=7.8 Hz,1H), 8.368-8.394(d, J=7.8 Hz,1H), 8.772(s,2H),10.638(s, 1H), 11.627(s, 1H)

EXAMPLE 81 N4-(3,5-dichloro-4-pyridyl)-6-chloro-1-methoxy-9H-4-carbazolecarboxamide

Step 1: 6-chloro-1-methoxy 9H-4-carbazole carboxylic acid

To a solution of intermediate 73b (400 mg, 1.38 mmoles) in methanol (15ml), an aqueous (5 ml) solution of sodium hydroxide (110 mg, 2.76mmoles) was added and the reaction mixture was refluxed for 6 hours.Methanol was evaporated from the reaction mixture under reducedpressure, the residue was acidified with 1N HCl and the precipitatedproduct was filtered, washed with water and dried under vacuum, to give380 mg of the title product.

IR (KBr, cm⁻¹): 565, 589, 631, 657, 745, 791, 885, 919, 989, 1015, 1066,1111, 1269, 1291, 1305, 1371, 1418, 1461, 1567, 1613, 1625, 1684, 2623,2849, 2939 and 3461.

¹H NMR (300 MHz, DMSO-d₆, δ): 4.065(s, 3H), 7.087-7.115 (d, J=8.4 Hz,1H), 7.399-7.437 (d, J=11.4 Hz, 1H), 7.505-7.534 (d, J=8.7 Hz, 1H),7.5-7.877 (d J=8.4 Hz, 1H), 8.96-8.967 (d, J=2.4 Hz, 1H),11.84 (s, 1H),12.8 (b s, 1H).

Step 2: 4-Nitrophenyl-6-chloro-1-methoxy 9H-4-carbazole carboxylate

To a suspension of 6-chloro-1-methoxy 9H-4-carbazole carboxylic acid(375 mg, 1.36 mmoles) in dry chloroform (15 ml), thionyl chloride (0.3ml, 4.08 mmoles) was added followed by 2 drops of dry DMF and stirredthe reaction mixture under nitrogen atmosphere for two hours. Solventand the excess thionyl chloride were evaporated from the reactionmixture and dried under vacuum. To this residue, dry chloroform (15 ml)was added followed by 4-nitrophenol (190 mg, 1.36 mmoles) andtriethylamine (0.29 ml, 2.04 mmoles) were added and the reaction mixturewas stirred under nitrogen atmosphere for 2 hours. The reaction mixturewas diluted with chloroform (30 ml) and washed with 1N HCl. The organiclayer was washed with brine (20 ml), dried over Na₂SO₄ and concentratedto give 0.38 gm of the title product as yellow solid.

IR (KBr, cm⁻¹): 3394, 2935, 1746, 1567, 1510, 1347, 1211, 1202, 1100,951 and 745.

¹H NMR (300 MHz, DMSO-d₆, δ): 4.13(s, 3H), 7.225-7.255 (d, J=9.0 Hz,1H), 7.438-7.476 (d, J=11.4 Hz, 1H), 7.552-7.581 (d, J=8.7 Hz, 1H),7.679-7.708 (d, J=8.7 Hz, 1H), 8.204-8.231 (d, J=8.1 Hz, 1H),8.364-8.395 (d, J=9.3 Hz, 1H), 8.832-8.839 (d, J=2.1 Hz, 1H),12.06 (s,1H).

Step 3: N4-(3,5-dichloro-4-pyridyl)-6-chloro-1-methoxy-9H-4-carbazolecarboxamide

To a solution of 4-Nitrophenyl-6-chloro-1-methoxy 9H-4-carbazolecarboxylate (100 mg, 0.345 mmoles) in dry DMF (5 ml),3,5-dichloro-4-amino pyridine (56 mg, 0.345 mmoles) was added followedby sodium hydride (60% suspension, 30 mg, 0.7 mmoles) and the reactionmixture was stirred at room temperature for 2 hours. Ice pieces wereadded to the reaction mixture and diluted with water. The pH of theabove emulsion was adjusted to neutral with 1N HCl and the precipitatedproduct was filtered, washed with water, followed by pet ether and driedunder vacuum to give 50 mg of the title compound as a pale yellow solid,m. p: >359° C.

IR (KBr, cm⁻¹): 3190, 2937, 1660, 1574, 1485, 1463, 1305, 1230, 1114,1022, 918 and 798.

¹H NMR (300 MHz, DMSO-d₆, δ): 4.083(s, 3H), 7.154-7.182 (d, J=8.4 Hz,1H), 7.383-7.419 (d, J=11.8 Hz, 1H), 7.507-7.536 (d, J=8.7 Hz, 1H),7.684-7.711 (d, J=8.1 Hz, 1H), 8.462-8.470 (d, J=2.4 Hz, 1H), 8.792 (s,2H), 10.701 (s, 1H),11.855 (s, 1H).

EXAMPLE 82N4-(3,5-dichloro-4-pyridyl)-9-benzyl-6-chloro-1-methoxy-9H-4-carbazolecarboxamide

Step 1: 6-chloro-1-methoxy 9H-4-carbazole carboxylic acid

To a solution of intermediate 73b (400 mg, 1.38 mmoles) in methanol (15ml), an aqueous (5 ml) solution of sodium hydroxide (110 mg, 2.76mmoles) was added and the reaction mixture was refluxed for 6 hours.Methanol was evaporated from the reaction mixture under reducedpressure, the residue was acidified with 1N HCl and the precipitatedproduct was filtered, washed with water and dried under vacuum, to give380 mg of the title product.

IR (KBr, cm⁻¹): 565, 589, 631, 657, 745, 791, 885, 919, 989, 1015, 1066,1111, 1269,1 291, 1305, 1371, 1418, 1461, 1567, 1613, 1625, 1684, 2623,2849, 2939 and 3461.

¹H NMR (300 MHz, DMSO-d₆, δ): 4.065(s, 3H), 7.087-7.115 (d, J=8.4 Hz,1H), 7.399-7.437 (d, J=11.4 Hz, 1H), 7.505-7.534 (d, J=8.7 Hz, 1H),7.5-7.877 (d, J=8.4 Hz, 1H), 8.96-8.967 (d, J=2.4 Hz, 1H),11.84 (s, 1H),12.8 (b s, 1H).

Step 2: 4-Nitrophenyl-6-chloro-1-methoxy 9H-4-carbazole carboxylate

To a suspension of 6-chloro-1-methoxy 9H-4-carbazole carboxylic acid(375 mg, 1.36 mmoles) in dry chloroform (15 ml), thionyl chloride (0.3ml, 4.08 mmoles) was added followed by 2 drops of dry DMF and stirredthe reaction mixture under nitrogen atmosphere for two hours. Solventand the excess thionyl chloride were evaporated from the reactionmixture and dried under vacuum. To this residue, dry chloroform (15 ml)was added followed by 4-nitrophenol (190 mg, 1.36 mmoles) andtriethylamine (0.29 ml, 2.04 mmoles) were added and the reaction mixturewas stirred under nitrogen atmosphere for 2 hours. The reaction mixturewas diluted with chloroform (30 ml) and washed with 1N HCl. The organiclayer was washed with brine (20 ml), dried over Na₂SO₄ and concentratedto give 0.38 gm of the title product as yellow solid.

IR (KBr, cm⁻¹): 3394, 2935, 1746, 1567, 1510, 1347, 1211, 1202, 1100,951 and 745.

¹H NMR (300 MHz, DMSO-d₆, δ): 4.13(s, 3H), 7.225-7.255 (d, J=9.0 Hz,1H), 7.438-7.476 (d, J=11.4 Hz, 1H), 7.552-7.581 (d, J=8.7 Hz, 1H),7.679-7.708 (d, J=8.7 Hz, 1H), 8.204-8.231 (d, J=8.1 Hz, 1H),8.364-8.395 (d, J=9.3 Hz, 1H), 8.832-8.839 (d, J=2.1 Hz, 1H),12.06 (s,1H).

Step 3: 4-Nitrophenyl 9-benzyl-6-chloro-1-methoxy-4-carbazolecarboxylate

To a solution of 4-Nitrophenyl-6-chloro-1-methoxy-9H-4-carbazolecarboxylate (0.38 gm, 0.958 mmoles) in dry DMF (10 ml) under nitrogenatmosphere at 0° C., sodium hydride (60% suspension, 60 mg, 1.44 mmoles)was added and the reaction mixture was stirred at room temperature for30 min. The reaction mixture was cooled to 0° C., benzyl bromide (0.12ml, 0.958 mmoles) was added and the reaction mixture was stirred at roomtemperature for 2 hours. Ice pieces were added to the reaction mixturefollowed by water (20 ml) and extracted with ethyl acetate (2×15 ml).The organic layer was washed with water (3×20 ml), brine (20 ml), driedover Na₂SO₄ and concentrated. The crude material was purified by columnchromatography to give 130 mg of the title compound.

IR (KBr, cm⁻¹): 3436, 3129, 2968, 1728, 1522, 1353, 1208, 1132, 1042,937 and 695.

¹H NMR (300 MHz, DMSO-d₆, δ): 4.032(s, 3H), 6.016 (s, 2H), 7.026-7.049(d, J=6.9 Hz, 2H), 7.186-7.312 (m, 4H), 7.509-7.546 (dd, J=8.7 Hz, 1H),7.707-7.769 (m, 3H), 8.24-8.268 (d, J=8.4 Hz, 1H), 8.39-8.42 (d, J=9.0Hz, 2H), 8.898-8.905 (d, J=2.1 Hz, 1H).

Step 4:N4-(3,5-dichloro-4-pyridyl)-9-benzyl-6-chloro-1-methoxy-9H-4-carbazolecarboxamide

To a solution of 4-Nitrophenyl 9-benzyl-6-chloro-1-methoxy-4-carbazolecarboxylate (124 mg, 0.255 mmoles) in dry DMF (3 ml) under nitrogenatmosphere, 3,5-dichloro-4-amino pyridine (41.5 mg, 0.255 mmoles) wasadded followed by sodium hydride (60% suspension, 16.7 mg, 0.382 mmoles)and the reaction mixture was stirred at room temperature for one hour.Ice pieces were added to the reaction mixture, diluted with water (15ml) and neutralized with 1N HCl. The precipitated product was filtered,washed with water, dried and purified by column chromatography to give60 mg of the title compound as an off white solid, m. p: 210-213° C.

IR (KBr, cm⁻¹): 3193, 2923, 1658, 1482, 1462, 1255, 1128, 1073, 1020,795 and 703.

¹H NMR (300 MHz, DMSO-d₆, δ): 3.97(s, 3H), 5.96 (s, 2H), 7.032-7.06 (d,J=8.4 Hz, 2H), 7.165-7.229 (m, 5H), 7.429-7.466 (dd, J=9.9 Hz, 1H),7.641-7.669 (d, J=8.4 Hz, 1H), 8.441-8.447 (d, J=1.8 Hz, 1H), 8.802 (s,2H), 10.81 (s, 1H).

EXAMPLE 83N4-(3,5-dichloro-4-pyridyl)-6-chloro-9-cyclohexylmethyl-1-methoxy-9H-4-carbazolecarboxamide

Step 1: 6-chloro-1-methoxy 9H-4-carbazole carboxylic acid

To a solution of intermediate 73b (400 mg, 1.38 mmoles) in methanol (15ml), an aqueous (5 ml) solution of sodium hydroxide (110 mg, 2.76mmoles) was added and the reaction mixture was refluxed for 6 hours.Methanol was evaporated from the reaction mixture under reducedpressure, the residue was acidified with 1N HCl and the precipitatedproduct was filtered, washed with water and dried under vacuum, to give380 mg of the title product.

IR (KBr, cm⁻¹): 565, 589, 631, 657, 745, 791, 885, 919, 989, 1015, 1066,1111, 1269, 1291, 1305, 1371, 1418, 1461, 1567, 1613, 1625, 1684, 2623,2849, 2939 and 3461.

¹H NMR (300 MHz, DMSO-d₆, δ): 4.065(s, 3H), 7.087-7.115 (d, J=8.4 Hz,1H), 7.399-7.437 (d, J=11.4 Hz, 1H), 7.505-7.534 (d, J=8.7 Hz, 1H),7.5-7.877 (d, J=8.4 Hz, 1H), 8.96-8.967 (d, J=2.4 Hz, 1H),11.84 (s, 1H),12.8 (b s, 1H).

Step 2: 4-Nitrophenyl-6-chloro-1-methoxy 9H-4-carbazole carboxylate

To a suspension of 6-chloro-1-methoxy 9H-4-carbazole carboxylic acid(375 mg, 1.36 mmoles) in dry chloroform (15 ml), thionyl chloride (0.3ml 4.08 mmoles) was added followed by 2 drops of dry DMF and stirred thereaction mixture under nitrogen atmosphere for two hours. Solvent andthe excess thionyl chloride were evaporated from the reaction mixtureand dried under vacuum. To this residue, dry chloroform (15 ml) wasadded followed by 4-nitrophenol (190 mg, 1.36 mmoles) and triethylamine(0.29 ml, 2.04 mmoles) were added and the reaction mixture was stirredunder nitrogen atmosphere for 2 hours. The reaction mixture was dilutedwith chloroform (30 ml) and washed with 1N HCl. The organic layer waswashed with brine (20 ml), dried over Na₂SO₄ and concentrated to give0.38 gm of the title product as yellow solid.

IR (KBr, cm⁻¹):3394, 2935, 1746, 1567, 1510, 1347, 1211, 1202, 1100, 951and 745.

¹H NMR (300 MHz, DMSO-d₆, δ): 4.13(s, 3H), 7.225-7.255 (d, J=9.0 Hz,1H), 7.438-7.476 (d, J=11.4 Hz, 1H), 7.552-7.581 (d, J=8.7 Hz, 1H),7.679-7.708 (d, J=8.7 Hz, 1H), 8.204-8.231 (d, J=8.1 Hz, 1H),8.364-8.395 (d, J=9.3 Hz, 1H), 8.832-8.839 (d, J=2.1 Hz, 1H),12.06 (s,1H).

Step 3: 4-Nitrophenyl 6-chloro-9-cyclohexylmethyl-1-methoxy-4-carbazolecarboxylate

To a solution of 4-Nitrophenyl 6-chloro-9H-1-methoxy-4-carbazolecarboxylate (200 mg, 0.69 mmoles) in dry DMF (10 ml) under nitrogenatmosphere, at 0° C., sodium hydride (60% suspension, 42 mg, 1.036mmoles) was added and the reaction mixture was stirred at roomtemperature for 30 min. The reaction mixture was cooled to 0° C.,cyclohexyl methyl bromide (0.096 ml, 0.69 mmoles) was added and thereaction mixture was stirred at room temperature for 24 hours. Thereaction mixture was diluted with ethyl acetate (25 ml), added 1N HCl(15 ml), shaken and separated the layers. The aqueous layer wasextracted with ethyl acetate (20 ml), combined the organic layers,washed with water (3×15 ml), dried over Na₂SO₄ and concentrated. Thecrude material was purified by column chromatography to give 60 mg ofthe title compound.

¹H NMR (300 MHz, DMSO-d₆, δ): 1.082 (m, 6H), 1.381-1.397 (b, 2H),1.565-1.626 (b, 2H), 1.81 (b, 1H), 4.011(s, 3H), 4.541-4.564 (d, J=6.9Hz, 2H), 7.258-7.286 (d, J=8.4 Hz, 1H), 7.5-7.536 (dd, J=8.7 Hz, 1H),7.682-7.711 (d, J=8.7 Hz, 2H), 7.736-7.767 (d, J=8.7 Hz, 1H), 8.2-8.226(d, J=8.1 Hz, 1H), 8.374-8.403 (d, J=8.7 Hz, 2H), 8.857-8.863 (d, J=1.8Hz, 1H).

Step 4:N4-(3,5-dichloro-4-pyridyl)-6-chloro-9-cyclohexylmethyl-1-methoxy-9H-4-carbazolecarboxamide

To a solution of 4-Nitrophenyl 9-cyclohexylmethyl-6-chloro-1-methoxy-4-carbazole carboxylate (55 mg, 0.1116 mmoles)in dry DMF (3 ml) under nitrogen atmosphere, 3,5-dichloro-4-aminopyridine (18.2 mg, 0.1116 mmoles) was added followed by sodium hydride(60% suspension, 9.0 mg, 0.2233 mmoles) and the reaction mixture wasstirred at room temperature for one hour. Ice pieces were added to thereaction mixture, diluted with water (15 ml) and neutralized with 1NHCl. The precipitated product was filtered, washed with water and driedunder vacuum to give 38 mg of the title compound as an off white solid,m. p: 247-249° C.

¹H NMR (300 MHz, DMSO-d₆, δ): 1.08 (m, 6H), 1.381-1.397 (b, 2H),1.565-1.626 (b, 2H), 1.81 (b, 1H), 4.056(s, 3H), 4.507-4.532 (d, J=7.5Hz, 2H), 7.183-7.211 (d, J=8.4 Hz, 1H), 7.44-7.477 (dd, J=8.7 Hz, 1H),7.611-7.637 (d, J=7.8 Hz, 1H), 7.684-7.713 (d, J=8.7 Hz, 1H),8.415-8.421 (d, J=1.8 Hz, 1H), 8.803 (s, 2H), 10.784 (s, 1H).

EXAMPLE 84N4-(3,5-dichloro-4-pyridyl)-6-chloro-9-(4-fluorobenzyl)-1-methoxy-9H-4-carbazolecarboxamide

Step 1: 6-chloro-1-methoxy 9H-4-carbazole carboxylic acid

To a solution of intermediate 73b (400 mg, 1.38 mmoles) in methanol (15ml), an aqueous (5 ml) solution of sodium hydroxide (110 mg, 2.76mmoles) was added and the reaction mixture was refluxed for 6 hours.Methanol was evaporated from the reaction mixture under reducedpressureor, the residue was acidified with 1N HCl and the precipitatedproduct was filtered, washed with water and dried under vacuum, to give380 mg of the title product.

IR (KBr, cm⁻¹): 565, 589, 631, 657, 745, 791, 885, 919, 989, 1015, 1066,1111, 1269, 1291, 1305, 1371, 1418, 1461, 1567, 1613, 1625, 1684, 2623,2849, 2939 and 3461.

¹H NMR (300 MHz, DMSO-d₆, δ): 4.065(s, 3H), 7.087-7.115 (d, J=8.4 Hz,1H), 7.399-7.437 (d, J=11.4 Hz, 1H), 7.505-7.534 (d, J=8.7 Hz, 1H),7.5-7.877 (d, J=8.4 Hz, 1H), 8.96-8.967 (d, J=2.4 Hz, 1H),11.84 (s, 1H),12.8 (b s, 1H).

Step 2: 4-Nitrophenyl-6-chloro-1-methoxy 9H-4-carbazole carboxylate

To a suspension of 6-chloro-1-methoxy 9H-4-carbazole carboxylic acid(375 mg, 1.36 mmoles) in dry chloroform (15 ml), thionyl chloride (0.3ml, 4.08 mmoles) was added followed by 2 drops of dry DMF and stirredthe reaction mixture under nitrogen atmosphere for two hours. Solventand the excess thionyl chloride were evaporated from the reactionmixture and dried under vacuum. To this residue, dry chloroform (15 ml)was added followed by 4-nitrophenol (190 mg, 1.36 mmoles) andtriethylamine (0.29 ml, 2.04 mmoles) were added and the reaction mixturewas stirred under nitrogen atmosphere for 2 hours. The reaction mixturewas diluted with chloroform (30 ml) and washed with 1N HCl. The organiclayer was washed with brine (20 ml), dried over Na₂SO₄ and concentratedto give 0.38 gm of the title product as yellow solid.

IR (Br, cm⁻¹): 3394, 2935, 1746, 1567, 1510, 1347, 1211, 1202, 1100, 951and 745.

¹H NMR (300 MHz, DMSO-d₆, δ): 4.13(s, 3H), 7.225-7.255 (d, J=9.0 Hz,1H), 7.438-7.476 (d, J=11.4 Hz, 1H), 7.552-7.581 (d, J=8.7 Hz, 1H),7.679-7.708 (d, J=8.7 Hz, 1H), 8.204-8.231 (d, J=8.1 Hz, 1H),8.364-8.395 (d, J=9.3 Hz, 1H), 8.832-8.839 (d, J=2.1 Hz, 1H),12.06 (s,1H).

Step 3: 4-Nitrophenyl 6-chloro-9-(4-fluoro benzyl)-1-methoxy-4-carbazolecarboxylate

To a solution of 4-Nitrophenyl 6-chloro-9H-1-methoxy-4-carbazolecarboxylate (200 mg, 0.69 mmoles) in dry DMF (10 ml) under nitrogenatmosphere, at 0° C., sodium hydride (60% suspension, 42 mg, 1.036rnmoles) was added and the reaction mixture was stirred at roomtemperature for 30 min. The reaction mixture was cooled to 0° C.,4-fluoro benzylbromide (0.086 ml, 0.69 mmoles) was added and stirred thereaction mixture at room temperature for 30 min. The reaction mixturewas diluted with ethyl acetate (25 ml), added 1N HCl (15 ml), shaken andseparated the layers. The aqueous layer was extracted with ethyl acetate(20 ml), combined the organic layers, washed with water (3×15 ml), driedover Na₂SO₄ and concentrated. The crude material was diluted with ethylacetate (20 ml) and allowed to stand at 10° C. for 10 min. The separatedsolid flakes were filtered, washed with pet ether and dried to give 176mg of the title compound.

IR (KBr, cm⁻¹): 2933, 1727, 1567, 1510, 1456, 1342, 1244, 1178, 1130,1042, 1013, 803 and 743.

¹H NMR (300 MHz, DMSO-d₆, δ): 4.031(s, 3H), 5.983 (s, 2H), 7.065-7.089(d, J=7.2 Hz, 4H), 7.274-7.303 (d, J=8.7 Hz, 1H), 7.51-7.547 (dd, J=9.0Hz, 1H), 7.693-7.724 (d, J=9.3 Hz, 2H), 7.757-7.786 (d, J=8.7 Hz, 1H),8.228-8.257 (d, J=8.7 Hz, 1H), 8.379-8.408 (d, J=8.7 Hz, 2H, 8.886-8.893(d, J=2.1 Hz, 1H).

Step 4:N4-3,5-dichloro-4-pyridyl)-6-chloro-9-(4-fluorobenzyl)-1-methoxy-9H-4-carbazolecarboxamide

To a solution of 4-Nitrophenyl 9-(4-fluorobenzyl)-6-chloro-1-methoxy-4-carbazole carboxylate (170 mg, 0.4276mmoles) in dry DMF (6 ml) under nitrogen atmosphere,3,5-dichloro-4-amino pyridine (69.7 mg, 0.1116 mmoles) was addedfollowed by sodium hydride (60% suspension, 37.0 mg, 0.8553 mmoles) andthe reaction mixture was stitted at room temperature for two hours. Icepieces were added to the reaction mixture, diluted with water (15 ml)and neutralized with 1N HCl. The precipitated product was filtered,washed with water and dried under vacuum to give 100 mg of the titlecompound as an off white solid, m. p: 249-250° C.

IR (KBr, cm⁻¹): 3189, 2938, 1651, 1509, 1488, 1462, 1399, 1310, 1272,1256, 1222, 1133, 1019, 815 and 795.

¹H NMR (300 MHz, DMSO-d₆, δ): 3.984(s, 3H), 5.94 (s, 2H), 7.065-7.104(m, 4H), 7.206-7.234 (d, J=8.4 Hz, 1H), 7.446-7.482 (dd, J=8.7 Hz, 1H),7.648-7.674 (d, J=7.8 Hz, 1H), 7.705-7.734 (d, J=8.7 Hz, 1H),8.444-8.451 (d, J=2.1 Hz, 1H), 8.805 (s, 2H), 10.81 (s, 1H).

EXAMPLE 85N4-(3,5-dichloro-4-pyridyl)-6-chloro-9-(4-methoxybenzyl)-1-methoxy-9H-4-carbazolecarboxamide

Step 1: 6-chloro-1-methoxy 9H-4-carbazole carboxylic acid

To a solution of intermediate 73b (400 mg, 1.38 mmoles) in methanol (15ml), an aqueous (5 ml) solution of sodium hydroxide (110 mg, 2.76mmoles) was added and the reaction mixture was refluxed for 6 hours.Methanol was evaporated from the reaction mixture under reducedpressure, the residue was acidified with 1N HCl and the precipitatedproduct was filtered, washed with water and dried under vacuum, to give380 mg of the title product

IR (KBr, cm⁻¹): 565, 589, 631, 657, 745, 791, 885, 919, 989, 1015, 1066,1111, 1269, 1291, 1305, 1371, 1418, 1461, 1567, 1613, 1625, 1684, 2623,2849, 2939 and 3461.

¹H NMR (300 MHz, DMSO-d₆, δ): 4.065(s, 3H), 7.087-7.115 (d, J=8.4 Hz,1H), 7.399-7.437 (d, J=11.4 Hz, 1H), 7.505-7.534 (d, J=8.7 Hz, 1H),7.5-7.877 (d, J=8.4 Hz, 1H), 8.96-8.967 (d, J=2.4 Hz, 1H),11.84 (s, 1H),12.8 (b s, 1H).

Step 2: 4-Nitrophenyl-6-chloro-1-methoxy 9H-4-carbazole carboxylate

To a suspension of 6-chloro-1-methoxy 9H-4-carbazole carboxylicacid (375mg, 1.36 mmoles) in dry chloroform (15 ml), thionyl chloride (0.3 ml,4.08 mmoles) was added followed by 2 drops of dry DMF and stirred thereaction mixture under nitrogen atmosphere for two hours. Solvent andthe excess thionyl chloride were evaporated from the reaction mixtureand dried under vacuum. To this residue, dry chloroform (15 ml) wasadded followed by 4-nitrophenol (190 mg, 1.36 mmoles) and triethylamine(0.29 ml, 2.04 mmoles) were added and the reaction mixture was stirredunder nitrogen atmosphere for 2 hours. The reaction mixture was dilutedwith chloroform (30 ml) and washed with 1N HCl. The organic layer waswashed with brine (20 ml), dried over Na₂SO₄ and concentrated to give0.38 gm of the title product as yellow solid.

IR (KBr, cm⁻¹): 3394, 2935, 1746, 1567, 1510, 1347, 1211, 1202, 1100,951 and 745.

¹H NMR (300 MHz, DMSO-d₆, δ): 4.13(s, 3H), 7.225-7.255 (d, J=9.0 Hz,1H), 7.438-7.476 (d, J=11.4 Hz, 1H), 7.552-7.581 (d, J=8.7 Hz, 1H),7.679-7.708 (d, J=8.7 Hz, 1H), 8.204-8.231 (d, J=8.1 Hz, 1H),8.364-8.395 (d, J=9.3 Hz, 1H), 8.832-8.839 (d, J=2.1 Hz, 1H),12.06 (s,1H).

Step 3: 4-Nitrophenyl 6-chloro-9-(4-methoxybenzyl)-1-methoxy-4-carbazole carboxylate

To a solution of 4-Nitrophenyl 6-chloro-9H-1-methoxy-4-carbazolecarboxylate (200 mg, 0.69 mmoles) in dry DMF (10 ml) under nitrogenatmosphere, at 0° C., sodium hydride (60% suspension, 42 mg, 1.036mmoles) was added and the reaction mixture was stirred at roomtemperature for 30 min. The reaction mixture was cooled to 0° C.,4-methoxy benzylchloride (0.094 ml, 0.69 mmoles) was added and stirredthe reaction mixture at room temperature for 30 min The reaction mixturewas diluted with ethyl acetate (25 ml), added 1N HCl (15 ml), shaken andseparated the layers. The aqueous layer was extracted with ethyl acetate(20 ml), combined the organic layers, washed with water (3×15 ml), driedover Na₂SO₄ and concentrated. The crude material was diluted with ethylacetate (20 ml) and allowed to stand at 10° C. for 10 min The separatedsolid flakes were filtered, washed with pet ether and dried to give 100mg of the title compound.

IR (KBr, cm⁻¹): 3434, 2837, 1726, 1565, 1523, 1514, 1461, 1353, 1252,1172, 1133, 1040, 1012 and 804.

¹H NMR (300 MHz, DMSO-d₆, δ): 3.653 (s, 3H), 4.064(s, 3H), 5.926 (s,2H), 6.774-6.803 (d, J=8.7 Hz, 2H), 6.996-7.026 (d, J=9.0 Hz, 2H),7.281-7.308 (d, J=8.1 Hz, 1H), 7.50-7.536 (dd, J=8.7 Hz, 1H),7.692-7.723 (d, J=9.3 Hz, 2H), 7.752-7.781 (d, J=8.7 Hz, 1H),8.225-8.252 (d, J=8.1 Hz, 1H), 8.377-8.408 (d, J=9.3 Hz, 2H),8.871-8.880 (d, J=2.7 Hz, 1H).

Step 4: N4-(3,5-dichloro-4-pyridyl)-6-chloro-9-4-methoxybenzyl)-1-methoxy-9H -4-carbazole carboxamide

To a solution of 4-Nitrophenyl 9-(4-methoxybenzyl)-6-chloro-1-methoxy-4-carbazole carboxylate (95 mg, 0.232 mmoles)in dry DMF (5 ml) under nitrogen atmosphere, 3,5-dichloro-4-aminopyridine (37.8 mg, 0.232 mmoles) was added followed by sodium hydride(60% suspension, 20.0 mg, 0.464 mmoles) and the reaction mixture wasstirred at room temperature for two hours. Ice pieces were added to thereaction mixture, diluted with water (15 ml) and neutralized with 1NHCl. The precipitated product was filtered, washed with water and driedunder vacuum to give 60 mg of the title compound as an off white solid,m. p: 257-258° C.

IR (KBr, cm⁻¹): 3240, 2933, 1666, 1512, 1478, 1461, 1304, 1255, 1128,1019 and 795.

¹H NMR (300 MHz, DMSO-d₆, δ): 3.649 (s, 3H), 4.017(s, 3H), 5.883 (s,2H), 6.772-6.801 (d, J=8.7 Hz, 2H), 7.018-7.045 (d, J=8.1 Hz, 2H),7.209-7.237 (d, J=8.4 Hz, 1H), 7.433-7.469 (dd, J=8.4 Hz, 1H),7.64-7.667 (d, J=8.1 Hz, 1H), 7.698-7.728 (d, J=9.0 Hz, 1H), 8.428-8.434(d, J=1.8 Hz, 1H), 8.803 (s, 2H), 10.805 (s, 1H).

EXAMPLE 86N4-(3,5-dichloro-4-pyridyl)-9-(4-fluorobenzyl)-1-methoxy-9H-4-carbazolecarboxamide

Step 1: 1-methoxy 9H-4-carbazole carboxylic acid

To a solution of intermediate 73a (800 mg, 2.7 mmoles) in methanol (25ml), an aqueous (10 ml) solution of sodium hydroxide (220 mg, 5.4mmoles) was added and the reaction mixture was refluxed for 6 hours.Methanol was evaporated from the reaction mixture under reducedpressureor, acidified the residue with 1N HCl and the precipitatedproduct was filtered, washed with water and dried under vacuum, to give780 mg of the title product.

¹H NMR (300 MHz, DMSO-d₆, δ): 4.21(s, 3H), 7.0-7.1 (d, J=8.4 Hz, 1H),7.1-7.2 (t, J=7.2 Hz, 1H), 7.4 (t, J=7.5 Hz, 1H), 7.5 (d, J=8.1 Hz, 1H),7.8 (d, J=8.4 Hz, 1H), 8.9 (d, J=8.1 Hz, 1H),11.6 (s, 1H), 12.6 (s, 1H).

Step 2: 4-Nitrophenyl-1-methoxy 9H-4-carbazole carboxylate

To a suspension of 1-methoxy 9H-4-carbazole carboxylic acid (800 mg, 3.3mmoles) in dry chloroform (15 ml), thionyl chloride (0.73 ml, 9.95mmoles) was added followed by 2 drops of dry DMF and stirred thereaction mixture under nitrogen atmosphere for two hours. Solvent andthe excess thionyl chloride were evaporated from the reaction mixtureand dried under vacuum. To this residue, dry chloroform (25 ml) wasadded followed by 4-nitrophenol (461 mg, 3.3 mmoles) and triethylamine(0.466 ml, 3.3 mmoles) were added and the reaction mixture was stirredunder nitrogen atmosphere for 2 hours. The reaction mixture was dilutedwith chloroform (30 ml) and washed with 1N HCl. The organic layer waswashed with brine (20 ml), dried over Na₂SO₄ and concentrated to give0.9 g of the title product as yellow solid.

IR (KBr, cm⁻¹): 3388, 2925, 1744, 1567, 1510, 1350, 1205, 1085, 951 and749.

¹H NMR (300 MHz, DMSO-d₆, δ): 4.127(s, 3H), 7.1-7.151 (t, J=7.8 Hz, 1H),7.191-7.220 (d, J=8.7 Hz, 1H), 7.404-7.454 (t, J=7.8 Hz, 1H),7.546-7.572 (d, J=7.8 Hz, 1H), 7.678-7.703 (d, J=7.5 Hz, 2H),8.158-8.186 (d, J=8.4 Hz, 1H), 8.371-8.396 (d, J=7.5 Hz, 2H),8.760-8.788 (d, J=8.4 Hz, 1H), 11.85 (s, 1H).

Step 3: 4-Nitrophenyl-9-(4-fluoro benzyl)-1-methoxy-4-carbazolecarboxylate

To a solution of 4-Nitrophenyl-9H-1-methoxy-4-carbazole carboxylate (130mg, 0.36 mmoles) in dry DMF (6 ml) under nitrogen atmosphere, at 0° C.,sodium hydride (60% suspension, 20 mg, 0.503 mmoles) was added and thereaction mixture was stirred at room temperature for 30 min. thereaction mixture was cooled to 0° C., 4-fluoro benzylbromide (0.045 ml,0.36 mmoles) was added and stirred the reaction mixture at roomtemperature for 30 min. The reaction mixture was diluted with ethylacetate (25 ml), added 1N HCl (15 ml), shaken and separated the layers.The aqueous layer was extracted with ethyl acetate (20 ml), combined theorganic layers, washed with water (3×15 ml), dried over Na₂SO₄ andconcentrated. The crude material was diluted with ethyl acetate (20 ml)and allowed to stand at 10° C. for 10 min. The separated solid flakeswere filtered, washed with pet ether and dried to give 150 mg of thetitle compound.

IR (KBr, cm⁻¹): 3398, 2924, 1742, 1513, 1457, 1344, 1215, 1047, 1011,924 and 744.

¹H NMR (300 MHz, DMSO-d₆, δ): 4.023(s, 3H), 5.974 (s, 2H), 7.058-7.099(m, 4H), 7.161-7.209 (t, J=7.2 Hz, 1H), 7.461-7.510 (t, J=7.2 Hz, 1H),7.684-7.715 (d, J=9.3 Hz, 2H), 8.017-8.049 (d, J=9.6 Hz, 1H),8.165-8.194 (d, J=8.7 Hz, 2H), 8.368-8.399 (d, J=9.3 Hz, 2H),8.785-8.811 (d, J=7.8 Hz, 1H).

Step 4:N4-(3,5-dichloro-4-pyridyl)-9-(4-fluorobenzyl)-1-methoxy-9H-4-carbazolecarboxamide

To a solution of 4-Nitrophenyl 9-(4-fluorobenzyl)-1-methoxy-9H-4-carbazole carboxylate (50 mg, 0.106 mmoles) indry DMF (4 ml) under nitrogen atmosphere, 3,5dichloro-4-amino pyridine(17.34 mg, 0.106 mmoles) was added followed by sodium hydride (60%suspension, 8.5 mg, 0.212 mmoles) and the reaction mixture was stirredat room temperature for two hours. Ice pieces were added to the reactionmixture, diluted with water (15 ml) and neutralized with 1N HCl. Theprecipitated product was filtered, washed with water and dried undervacuum to give 15 mg of the title compound as an off white solid, m.p:222-225° C.

IR (KBr, cm⁻¹): 3503, 3207, 1662, 1509, 1483, 1462, 1403, 1319, 1257,1221, 1118, 1014, 820 and 749.

¹H NMR (300 MHz, DMSO-d₆, δ): 3.974(s, 3M), 5.934 (s, 2H), 7.057-7.183(m, 6H), 7.396-7.445 (t, J=7.5 Hz, 1H), 7.594-7.622 (d, J=7.8 Hz, 1H),7.635-7.663 (d, J=8.4 Hz, 1H), 8.348-8.374 (d, J=7.8 Hz, 1H), 8.780 (s,2H), 10.738 (s, 1H).

EXAMPLE 87 N4-(4-pyridyl)-9-(4-fluorobenzyl)-1-methoxy-9H-4-carbazolecarboxamide

Step 1: Methyl 9-(4-fluoro benzyl)-1-methoxy-4-carbazole carboxylate

To a solution of intermediate 73a (400 mg, 1.568 mmoles) in dry DMF (15ml) under nitrogen atmosphere, at 0° C., sodium hydride (60% suspension,88 mg, 2.19 mmoles) was added and the reaction mixture was stirred atroom temperature for 30 min. The reaction mixture was cooled to 0° C.,4-fluoro benzylbromide (0.2 ml, 1.568 mmoles) was added and stirred thereaction mixture at room temperature for 30 min. The reaction mixturewas diluted with ethyl acetate (25 ml), added 1N HCl (15 ml), shaken andseparated the layers. The aqueous layer was extracted with ethyl acetate(20 ml), combined the organic layers, washed with water (3×15 ml), driedover Na₂SO₄ and concentrated to give 500 mg of the title compound.

¹H NMR (300 MHz, DMSO-d₆, δ): 3.942 (s, 3H), 3.965 (s, 3H), 5.929 (s,2H), 7.045-7.141 (m, 5H), 7.170-7.219 (t, J=7.5 Hz, 1H), 7.433-7.485 (t,J=7.2 Hz, 1H), 7.643-7.671 (d, J=8.4 Hz, 1H), 7.780-7.807 (d, J=8.1 Hz,1H), 8.748-8.774 (d, J=7.8 Hz, 1H).

Step 2: 9-(4-fluoro benzyl)-1-methoxy-4-carbazole carboxylic acid

To a solution of 9-(4-fluoro benzyl)-1-methoxy-4-carbazole carboxylicacid methyl ester (490 mg, 1.35 mmoles) in methanol (15 ml), an aqueous(10 ml) solution of sodium hydroxide (108 mg, 2.7 mmoles) was added andthe reaction mixture was refluxed for 6 hours. Methanol was evaporatedfrom the reaction mixture under reduced pressure, acidified the residuewith 1N HCl and the precipitated product was filtered washed with waterand dried under vacuum, to give 420 mg of the title product

IR (KBr, cm⁻¹): 3436, 2839, 1689, 1565, 1462, 1277, 1260, 1217, 1012 and740.

¹H NMR (300 MHz, DMSO-d₆, δ): 3.955 (s, 3H), 5.924 (s, 2H), 7.014-7.105(m, 5H), 7.152-7.203 (t, J=7.5 Hz, 1H), 7.417-7.466 (t, J=7.5 Hz, 1H),7.622-7.650 (d, J=8.4 Hz, 1H), 7.784-7.814 (d, J=9.0 Hz, 1H),8.876-8.902 (d, J=7.8 Hz, 1H), 12.751 b s, 1H).

Step 3: N4-(4-pyridyl)-9-4-fluorobenzyl)-1-methoxy 9H-4-carbazolecarboxamide

To a suspension of 9-(4-fluoro benzyl)-1-methoxy 9H-4-carbazolecarboxylicacid (100 mg, 0.286 mmoles) in dry chloroform (15 ml), thionylchloride (0.063 ml, 0.86 mmoles) was added followed by 2 drops of dryDMF and the reaction mixture was sired under nitrogen atmosphere for twohours. Solvent and the excess thionyl chloride were evaporated from thereaction mixture and dried under vacuum. To this residue, dry chloroform(15 ml) was added followed by 4-aminopyridine (27 mg, 0.286 mmoles) andtriethylamine (0.06 ml, 0.43 mmoles) were added and the reaction mixturewas stirred under nitrogen atmosphere for 17 hours. The reaction mixturewas diluted with chloroform (30 ml) and washed with water (2×10 ml). Theorganic layer was washed with brine (20 ml), dried over Na₂SO₄ andconcentrated to give 45 mg of the title product as pale yellow solid,m.p: 230-232° C.

IR (KBr, cm⁻¹): 3306, 2964, 1682, 1594, 1509, 1462, 1328, 1296, 1256,1209, 1114, 1015, 827 and 745.

¹H NMR (300 MHz, DMSO-₆, δ): 3.968 (s, 3H), 5.924 (s, 2H), 7.063-7.160(m, 6H), 7.431-7.458 (m, 2H), 7.653-7.681 (d, J=8.4 Hz, 1H), 7.786-7.804(d, J=5.4 Hz, 2H), 8.122-8.149 (d, J=8.7 Hz, 2H), 10.868 (s, 1H).

EXAMPLE 88N4-(3,5-dichloro-4-pyridyl)-9-benzyl-1-methoxy-9H-4-carbazolecarboxamide

Step 1: Methyl-9-benzyl-1-methoxy-9H-4-carbazolecarboxylate

To a solution of intermediate 73a (417 mg, 1.635 mmoles) in dry DMF (10ml), under N₂ atmosphere, 60% sodium hydride (107.04 mg, 2.453 mmoles)was added at 0° C. and the reaction mixture was stirred at 0° C. for 15min and at 25° C. for 30 min. then benzyl bromide (0.22 ml, 1.799mmoles) was added to the reaction mixture at 0° C., stirred for 15 minat 0° C. and then at 25° C. for 1 hr.

The reaction mixture was poured into ice-cold water and acidified with1N HCl. The compound was extracted with ethyl acetate (3×10 ml),combined the organic layers and washed with water (10 ml) and with brine(10 ml). The organic layer was dried over anhydrous sodium sulphate andconcentrated to yield 624 mg of the title compound as a white solid.

IR(KBr,cm⁻¹): 669, 758, 768, 1018, 1087, 1120, 1216, 1252, 1301, 1319,1435, 1453, 1461, 1522, 1570, 1595, 1710, 2400, 2855, 2928, 3019 and3400

¹H NMR (300 MHz, DMSO-d₆, δ):3.943(s,3H),3.953(s,3H),5.950(s,2H),7.031-7.052(d, J=6.3 Hz,2H),7.138-7.347(m,5H),7.411-7.476(t,J=8.7 Hz,1H),7.614-7.641(d,J=8.1 Hz,1H), 7.778-7.806 (d,J=8.4Hz,1H),8.748-8.776(d,J=8.4 Hz,1H)

Step 2: 9-benzyl-1-methoxy-9H-4-carbazolecarboxylic acid

To a solution of methyl-9-benzyl-1-methoxy-9H-4-carbazolecarboxylate(612 mg, 1.773 mmoles) aqueous sodium hydroxide (71mg, 1.773 mmoles) wasadded and the reaction mixture was refluxed for 1 hr. Methanol wasevaporated under reduced pressure, the reaction mixture was acidifiedwith 1N HCl and filtered to yield 430 mg of title compound as off-whitesolid.

IR(KBr,cm⁻¹): 522, 584, 629, 679, 695, 729, 742, 785, 1015, 1072, 1089,1122, 1221, 1246, 1263, 1303, 1320, 1358, 1413, 1443, 1452, 1462, 1564,1592, 1671, 1860, 2619, 2854, 2933 and 3030

¹H NMR (300 MHz,DMSO-d₆,δ): 3.945 (s,3H), 5.947 (s,2H), 7.032-7.055(d,J=6.9 Hz,2H), 7.149-7.347 (m,5H), 7.403-7.455 (t,J=7.8 Hz,1H),7.594-7.620 (d,J=7.8 Hz,1H), 7.783-7.810 (d,J=8.1 Hz,1H), 8.875-8.902(d,J=8.1 Hz,1H)

Step 3: 4-nitrophenyl-9-benzyl-1-methoxy-9H-4-carbazolecarboxylate

To a solution of 9-benzyl-1-methoxy-9H-4-carbazolecarboxylic acid (430mg, 1.299 moles) in dry chloroform (10 ml), thionyl chloride (0.28 ml,3.90 mmoles) was introduced followed by two drops of dry DMF at 25° C.under anhydrous conditions.

After complete conversion of acid to acid chloride, chloroform andthionyl chloride were evaporated under reduced pressure to give yellowcolored solid acid chloride, it was flushed with nitrogen to removetraces of thionyl chloride and then dissolved in dry chloroform (10 ml).p-nitrophenol (181 mg, 1.299 mmoles) and triethyl amine (0.24 ml, 1.688mmoles) was added to the reaction mixture at 25° C., under nitrogenatmosphere, the reaction mixture was stirred for half an hour. Thereaction mixture was diluted with chloroform (10 ml) and washed withwater (15 ml) followed by brine (10 ml). The organic layer was driedover anhydrous sodium sulphate and concentrated to give 420 mg of thecrude compound which was purified by column chromatography to yield 239mg of the title compound as yellow solid.

IR(KBr,cm⁻¹): 554, 567, 647, 679, 695, 732, 745, 781,8 08, 861, 936,1011, 1026, 1050, 1121, 1177, 1205, 1244, 1270, 1303, 1318, 1345, 1406,1463, 1491, 1522, 1562, 1591, 1613, 1731, 2854, 2924, 2956 and 3433

¹H NMR (300 MHz,DMSO-d₆,δ): 4.020 (s,3H), 6.002 (s,2H), 7.040-7.063(d,J=6.9 Hz,2H), 7.188-7.258 (m,5H), 7.455-7.505 (t,J=7.5 Hz,1H),7.669-7.721 (m,3H), 8.171-8.199 (d,J=8.4 Hz,1H) 8.376-8.403 (d,J=8.1Hz,2H), 8.793-8.821 (d,J=8.4 Hz,1H)

Step 4:N4-(3,5-dichloro-4-pyridyl)-9-benzyl-1-methoxy-9H-4-carbazolecarboxamide

To a solution of4-nitrophenyl-9-benzyl-1-methoxy-9H-4-carbazolecarboxylate (229 mg,0.506 mmoles) and 3,5-dichloro-4-aminopyridine (82.53 mg, 0.506 mmoles)in dry DMF (10 ml), under N₂ atmosphere, 60% sodium hydride (44.19 mg,1.012 mmoles) was added at 25° C. and the reaction mixture was stirredovernight. The reaction mixture was poured into ice-cold water andneutralized with 1N HCl. The compound was extracted with chloroform(2×15ml), combined the organic layers and washed with water (3×15 ml)and with brine (15 ml). The organic layer was dried over anhydroussodium sulphate and concentrated to give 200 mg of the crude compoundwhich was purified by column chromatography to yield 139 mg of the titlecompound as light brown colored solid, m.p: 215-217° C.

IR (KBr, cm⁻¹): 747, 1015, 1256, 1451, 1653, 1815 and 3217.

¹H NMR (300 MHz, DMSO-d₆, δ): 3.97(s, 3H), 5.96 (s, 2H), 7.05-7.23 (m,7H), 7.39-7.44 (m, 1H), 7.60-7.64 (d, J=8.1 Hz, 2H), 8.36-8.38 (d, J=7.8Hz, 1H), 8.79 (S, 2H), 10.75 (s, 1H).

EXAMPLE 89N4-(3,5-dichloro-4-pyridyl)-9-benzyl-1ethoxy-9H-4-carbazolecarboxamide

Step 1: Methyl-9-benzyl-1-ethoxy-9H-4-carbazolecarboxylate

To a solution of intermediate 80a (469 mg, 1.740 mmoles) in dry DMF (10ml), under N₂ atmosphere, 60% sodium hydride (113.88 mg, 2.610 mmoles)was added at 0° C. and the reaction mixture was stirred at 0° C. for 15min and at 25° C. for 30 min. then benzyl bromide (0.23 ml, 1.914mmoles) was added to the reaction mixture at 0° C., stirred for 15 minat 0° C. and then at 25° C. for 1 hr. The reaction mixture was pouredinto ice-cold water and acidified with 1N HCl. The compound wasextracted with ethyl acetate (3×10 ml), combined the organic layers andwashed with water (10 ml) and with brine (10 ml). The organic layer wasdried over anhydrous sodium sulphate and concentrated to yield 730 mg ofthe title compound as brown solid.

IR(KBr,cm⁻¹): 553, 577, 639, 697, 735, 748, 945, 1026, 1085, 1120, 1154,1210, 1252, 1272, 1301, 1325, 1394, 1407, 1435, 1452, 1464, 1567, 1711and 2925.

¹HNMR(300 MHz,DMSO-₆,δ):1.248-1.295 (t,J=6.9 Hz,3H), 3.942(s,3H),4.169-4.237 (q,J=6.9 Hz,2H),5.974(s,2H),6.992-7.014(d,J=6.6Hz,1H),7.071-7.099 (d,J=8.4 Hz,1H), 7.152-7.240(m,5H),7.425-7.474(t,J=7.4 Hz,1H), 7.611-7.638(d,J=8.1 Hz,1H), 7.758-7.786(d,J=8.4 Hz,1H), 8.763-8.789(d,J=7.8 Hz,1H)

Step 2: 9-Benzyl-1-ethoxy-9H-4-carbazolecarboxylic acid

To a solution of methyl-9-benzyl-1-ethoxy-9H-4-carbazolecarboxylate (728mg, 2.027 mmoles), in methanol (10 ml), aqueous sodium hydroxide (81 mg,2.027 mmoles) was added and the reaction mixture was refluxed for 1 hr.Methanol was evaporated under reduced pressure, the reaction mixture wasacidified with 1N HCl and filtered to yield 599 mg of title compound asan off-white solid.

IR(KBr,cm⁻¹): 522, 638, 694, 729, 743, 786, 815, 833, 956, 1027, 1086,1122, 1161, 1221, 1245, 1263, 1299, 1322, 1364, 1395, 1414, 1442, 1451,1462, 1565, 1588, 1673, 1867, 2625 and 2924.

¹H NMR(300 MHz, DMSO-d₆,δ): 1.251-1.297 (t,J=6.9 Hz,3H),4.166-4.211(q,J=6.9 Hz,2H), 5.974 (s,2H), 6.998-7.022 (d,T=7.2 Hz,1H),7.050-7.079 (d,J=8.7 Hz,1H), 7.152-7.221(m,5H), 7.406-7.458 (t,J=7.8Hz,1H), 7.589-7.617 (d,J=8.4 Hz,1H), 7.763-7.789 (d,J=7.8 Hz,1H),8.891-8.919 (d,J=8.4 Hz,1H)

Step 3: 4-Nitrophenyl-9-benzyl-1-ethoxy-9H-4-carbazolecarboxylate

To a solution of 9-benzyl-1-ethoxy-9H-4-carbazolecarboxylic acid (593mg, 1.718 moles) in dry chloroform (15 ml), thionyl chloride (0.38 ml,5.154 mmoles) was introduced followed by two drops of dry DMF at 25° C.under anhydrous conditions.

After complete conversion of acid to acid chloride, chloroform andthionyl chloride were evaporated under reduced pressure to give yellowcolored solid acid chloride, it was flushed with nitrogen to removetraces of thionyl chloride and then dissolved in dry chloroform (15 ml).p-nitrophenol (239 mg, 1.718 mmoles) and triethyl amine (0.36 ml, 2.577mmoles) was added to the reaction mixture at 25° C., under nitrogenatmosphere, the reaction mixture was stirred for half an hour. Thereaction mixture was diluted with chloroform (10 ml) and washed withwater (15 ml) followed by brine (10 ml). The organic layer was driedover anhydrous sodium sulphate and concentrated to give 520 mg of thecrude compound which was purified by column chromatography to yield 136mg of the title compound as yellow solid.

IR(KBr,cm⁻¹): 614, 648, 685, 700, 745, 833, 916, 948, 1009, 1029, 1053,1117, 1132, 1148, 1214, 1252, 1319, 1274, 1345, 1392, 1404, 1453, 1487,1522, 1560, 1591, 1613, 1730, 2932 and 2973.

¹H NMR(300 MHz,DMSO-₆,δ): 1.277-1.324 (t,J=7.1 Hz,3H), 4.237-4.307(q,J=7.1 Hz,2H), 6.022(s,2H), 6.993-7.014(d,J=6.3 Hz,2H),7.157-7.261(m,5H), 7.450-7.5 (t,J=7.3 Hz,1H), 7.661-7.716(m,3H),8.147-8.176(d,J=8.7 Hz,1H), 8.369-8.4(d,J=7.1 Hz,2H), 8.803-8.829(d,J=7.8 Hz,1H)

Step 4:N4-(3,5-dichloro-4-pyridyl)-9-benzyl-1-ethoxy-9H-4-carbazolecarboxamide

To a solution of4-nitrophenyl-9-benzyl-1-ethoxy-9H-4-carbazolecarboxylate (123 mg, 0.264mmoles) and 3,5 dichloro-4-aminopyridine (43 mg, 0.264 mmoles) in dryDMF (5 ml), under N₂ atmosphere, 60% sodium hydride (23.02 mg, 0.528)was added at 25° C. and the reaction mixture was stirred overnight. Thereaction mixture was poured into ice-cold water and neutralized with 1NHCl. The compound was extracted with chloroform (3×15 ml), combined theorganic layers and washed with water (3×15 ml) and with brine (15 ml).The organic layer was dried over anhydrous sodium sulphate andconcentrated to

IR (KBr, cm⁻): 748, 1120, 1255, 1452, 1463, 1485, 1572, 1659, 2927 and3210.

⁻¹H NMR (300 MHz, DMSO-d₆, δ): 1.232-1.319 (t, J=6.75 Hz,3H),4.184-4.252 (q, J=6.9 Hz 2H), 5.983(s,2H), 7.016-7.251(m,7H),7.386-7.435 (t, J=7.35 Hz,1H), 7.578-7.635 (t, J=8.55 Hz,2H),8.360-8.386 (d, J=7.8 Hz,1H), 8.780 (s,2H), 10.737 (s,1H)

EXAMPLE 90N4-(3,5-dichloro-4-pyridyl)-9-benzyl-6-chloro-1-ethoxy-9H-4-carbazolecarboxamide

Step 1: Methyl-9-benzyl-6-chloro-1-ethoxy-9H-4-carbazolecarboxylate

To a solution of intermediate 80b (86 mg, 0.283 mmoles) in dry DMF (3ml), under N₂ atmosphere, 60% sodium hydride (18.55 mg, 0.425 mmoles)was added at 0° C. and the reaction mixture was stirred at 0° C. for 15min and at 25° C. for 30 min. then benzyl bromide (0.04 ml, 0.315mmoles) was added to the reaction mixture at 0° C., stirred for 15 minat 0° C. and then at 25° C. for 1 hr. The reaction mixture was pouredinto ice-cold water and acidified with 1N HCl. The compound wasextracted with ethyl acetate (2×10 ml), combined the organic layers andwashed with water (10 ml) and with brine (10 ml). The organic layer wasdried over anhydrous sodium sulphate and concentrated to yield 114 mg ofthe title compound as a brown solid.

IR(KBr,cm⁻¹): 456, 554, 613, 640, 695, 730, 749, 783, 845, 897, 967,1035, 1071, 1093, 1129, 1189, 1212, 1259, 1308, 1379, 1394, 1435, 1451,1495, 1568, 1591, 1706, 2854 and 2925.

¹HNMR(300 MHz,DMSO-d₆, δ):1.228-1.293 (t,J=6.9 Hz,3H), 3.945(s,3H),4.177-4.246 (q,J=6.9 Hz,2H), 5.979(s,2H),6.970-6.992 (d,J=6.6 Hz,1H),7.117-7.250 (m,5H), 7.471-7.507 (dd,J=8.9 Hz,1H), 7.674-7.705 (d,J=9.3Hz,1H), 7.835-7.862 (d,J=8.1 Hz, 1H), 8.919-8.925 (d,J=1.8 Hz,1H)

Step 2: 9-Benzyl-6-chloro-1-ethoxy-9H-4-carbazolecarboxylic acid

To a solution ofmethyl-9-benzyl-6-chloro-1-ethoxy-9H-4-carbazolecarboxylate (110 mg,0.280 mmoles) aqueous sodium hydroxide (11.18 mg, 0.280 mmoles) wasadded and the reaction mixture was refluxed for 1 hr. Methanol wasevaporated under reduced pressure, the reaction mixture was acidifiedwith 1N HCl and filtered to yield 98 mg of title compound as off-whitesolid.

IR(KBr,cm⁻¹): 527, 557, 640, 658, 693, 729, 752, 785, 817, 847, 892,918, 1032, 1072, 1093, 1129, 1267, 1307, 1324, 1365, 1392, 1416, 1450,1496, 1567, 1590, 1678 and 2924.

¹H NMR(300 MHz,DMSO-d₆,δ): 1.222-1.290 (t,J=6.9 Hz,3H), 4.168-4.237(q,J=6.9 Hz,2H), 5.974(s,2H), 6.975-7.001 (d,J=7.1 Hz,1H), 7.092-7.251(m,5H),7.450-7.487 (dd,J=8.7 Hz,1H), 7.653-7.682 (d, J=8.7 Hz, 1H),7.827-7.854 (d, J=8.1 Hz, 1H), 9.0-9.008 (d,J=2.4 Hz,1H), 12.823(bs,1H).

Step 3: Preparation of4-nitrophenyl-9-benzyl-6-chlor-1-ethoxy-9H-4-carbazole carboxylate

To a solution of 9-benzyl-6-chloro-1-ethoxy-9H-4-carbazolecarboxylicacid (91 mg, 0.240 moles) in dry chloroform (10 ml), thionyl chloride(0.053 ml, 0.719 mmoles) was introduced followed by two drops of dry DMFat 25° C. under anhydrous conditions.

After complete conversion of acid to acid chloride, chloroform andthionyl chloride were evaporated under reduced pressure to give yellowcolored solid acid chloride, it was flushed with nitrogen to removetraces of thionyl chloride and then dissolved in dry chloroform (10 ml).p-nitrophenol (33.34 mg, 0.240 mmoles) and triethyl amine (0.05 ml,0.360 mmoles) was added to the reaction mixture at 25° C., undernitrogen atmosphere, the reaction mixture was stirred for half an hour.The reaction mixture was diluted with chloroform (10 ml) and washed withwater (15 ml) followed by brine (10 ml). The organic layer was driedover anhydrous sodium sulphate and concentrated to give 55 mg of thecrude compound which was purified by column chromatography to yield 33mg of the title compound as a yellow solid.

IR(KBr,cm⁻¹): 496, 642, 696, 736, 805, 844, 881, 897, 915, 962, 1026,1051, 1129, 1155, 1195, 1214, 1247, 1290,.1324, 1346, 1392, 1451, 1491,1523, 1562, 1592, 1615, 1722, and 2924.

¹HNMR(300 MHz, DMSO-d₆,δ): 1.232-1.295 (t,J=6.9 Hz,3H), 4.267-4.289(q,J=6.9 Hz,2H), 6.026(s,2H), 6.879-6.909 (d,J-9.0 Hz,2H), 6.967-6.990(d, J=6.9 Hz, 1H), 7.172-7.264 (m,3H), 7.495-7.533 (dd,J=8.9 Hz,1H),7.692-7.755 (m,3H), 8.077-8.108 (d,J=9.3 Hz,2H), 8.374-8.405 (d,J=9.3Hz,1H), 8.897-8.904 (d, J=2.1 Hz, 1H).

Step 4:N4-(3,5-dichloro-4-pyridyl)-9-benzyl-6-chloro-1-ethoxy-9H-4-carbazolecarboxamide

To a solution of 4-nitrophenyl9-benzyl-6-chloro-1-ethoxy-9H-4-carbazolecarboxylate (31 mg, 0.062mmoles) and 3,5 dichloro-4-aminopyridine (10.1 mg, 0.062 mmoles) in dryDMF (3 ml), under N₂ atmosphere, 60% sodium hydride (5.40 mg, 0.124mmoles) was added at 25° C. and the reaction mixture was stirredovernight. The reaction mixture was poured into ice-cold water andneutralized with 1N HCl. The compound was extracted with chloroform(3×10 ml), combined the organic layers and washed with water (3×10 ml)and with brine (10 ml). The organic layer was dried over anhydroussodium sulphate and concentrated to give 22.5 mg of the title compoundas an off-white crystalline solid. m.p: 221 -223° C.

IR (KBr, cm⁻¹): 795, 1133, 1259, 1269, 1452, 1463, 1487, 1570, 1650,2924 and 3178.

¹H NMR (300 MHz, DMSO-d₆, δ): 1.269-1.314 (t, J=6.75 Hz,3H), 4.187-4.255(q, J=6.75 Hz 2H), 5.981 (s,2H), 6.993-7.014 (d, J=6.3 Hz 2H),7.165-7.255 (m,4H), 7.429-7.464 (dd, J=8.7 Hz,1H), 7.622-7.700 (m,2H),8.446-8.452(d, J=1.8 Hz,1H), 8.798(s,2H), 10.803 (s,1H)

EXAMPLE 91 N4-(4-pyridyl)-9-benzyl-1-ethoxy-9H-4-carbazolecarboxamide

Step 1: Methyl-9-benzyl-1-ethoxy-9H-4-carbazolecarboxylate

To a solution of intermediate 80a (469 mg, 1.740 mmoles) in dry DMF (10ml), under N₂ atmosphere, 60% sodium hydride (113.88 mg, 2.610 mmoles)was added at 0° C. and the reaction mixture was stirred at 0° C. for 15min and at 25° C. for 30 min. then benzyl bromide (0.23 ml, 1.914mmoles) was added to the reaction mixture at 0° C., stirred for 15 minat 0° C. and then at 25° C. for 1 hr. The reaction mixture was pouredinto ice-cold water and acidified with 1N HCl. The compound wasextracted with ethyl acetate (3×10 ml), combined the organic layers andwashed with water (10 ml) and with brine (10 ml). The organic layer wasdried over anhydrous sodium sulphate and concentrated to yield 730 mg ofthe title compound as a brown solid.

IR(KBr,cm⁻¹): 553, 577, 639, 697, 735, 748, 945, 1026, 1085, 1120, 1154,1210, 1252, 1272, 1301, 1325, 1394, 1407, 1435, 1452, 1464, 1567, 1711and 2925.

¹HNMR(300 MHz,DMSO-d₆,δ): 1.248-1.295 (t,J=6.9 Hz,3H), 3.942(s,3H),4.169-4.237 (q,J=6.9 Hz,2H), 5.974 (s,2H), 6.992-7.014(d,J=6.6Hz,1H), 7.071-7.099 (d,J=8.4 Hz,1H), 7.152-7.240 (m,5H), 7.425-7.474(t,J=7.4 Hz,1H), 7.611-7.638 (d,J=8.1 Hz,1H), 7.758-7.786 (d,J=8.4Hz,1H), 8.763-8.789 (d,J=7.8 Hz,1H)

Step 2: 9-Benzyl-1-ethoxy-9H-4-carbazolecarboxylic acid

To a solution of methyl-9-benzyl-1-ethoxy-9H-4-carbazolecarboxylate (728mg, 2.027 mmoles) aqueous sodium hydroxide (81 mg, 2.027 mmoles) wasadded and the reaction mixture was refluxed for 1 hr. Methanol wasevaporated under reduced pressure, the reaction mixture was acidifiedwith 1N HCl and filtered to yield 599 mg of title compound as anoff-white solid

IR(KBr,cm⁻¹): 522, 638, 694, 729, 743, 786, 815, 833, 956, 1027, 1086,1122, 1161, 1221, 1245, 1263, 1299, 1322, 1364, 1395, 1414, 1442, 1451,1462, 1565, 1588, 1673, 1867, 2625 and 2924.

¹H NMR(300 MHz, DMSO-d₆,δ): 1.251-1297 (t,J=6.9 Hz,3H), 4.166-4.211(q,J=6.9 Hz,2H), 5.974 (s,2H), 6.998-7.022 (d,J=7.2 Hz 1H), 7.050-7.079(d,J=8.7,1H), 7.152-7.221 (m,5H), 7.406-7.458 (t,J=7.8 Hz,1H),7.589-7.617 (d,J=8.4 Hz,1H), 7.763-7.789 (d,J=7.8 Hz,1H), 8.891-8.919(d,J=8.4 Hz,1H)

Step 3: N4-(4-pyridyl)-9-benzyl-1-ethoxy-9H-4-carbazolecarboxamide

To a solution of 9-benzyl-1-ethoxy-9H-4-carbazolecarboxylic acid (57 mg,0.165 moles) in dry chloroform (5 ml), thionyl chloride (0.04 ml, 0.495mmoles) was introduced followed by two drops of dry DMF at 25° C. underanhydrous conditions.

After complete conversion of acid to acid chloride, chloroform andthionyl chloride were evaporated under reduced pressure to give yellowcolored solid acid chloride, it was flushed with nitrogen to removetraces of thionyl chloride and then dissolved in dry chloroform (5 ml).4-amino pyridine (15.54 mg, 0.165 mmoles) and triethyl amine (0.04 ml0.248 mmoles) was added to the reaction mixture at 25° C., undernitrogen atmosphere, the reaction mixture was stirred overnight.

The reaction mixture was diluted with chloroform (10 ml) and washed withwater (15 ml) followed by brine (5 ml). The organic layer was dried overanhydrous sodium sulphate and concentrated to give 90 mg of the crudecompound which was purified by column chromatography to yield 74 mg ofthe title compound as an off-white solid, m.p: 242-244° C.

IR (KBr, cm⁻): 733, 747, 1116, 1207, 1257, 1294, 1328, 1510, 1572, 1594,1689, 2923 and 3222.

¹H NMR (300 MHz, DMSO-d₆, δ): 1.266-1.313 (t, J=7.05 Hz,3H), 4.176-4.244(q, J=6.75 Hz 2H), 5.976(s,2H), 7.024-7.256(m, 7H), 7.388 (s,1H),7.409-7.435(d, J=7.8 Hz,1H), 7.622-7.650 (d, J=8.4 Hz,1H), 7.789-7.809(d, J=6 Hz, 2H), 8.139-8.165 (d, J=7.8 Hz,1H), 8.475-8.493 (d, J=5.4 Hz,2H), 10.867 (s,1H)

EXAMPLE 92N4-(3-pyridyl)-6-chloro-9-(4-fluorobenzyl)-1-methoxy-9H-4-carbazolecarboxamide

To a solution of intermediate 82 (100 mg, 0.251 mmoles) in drychloroform (5 ml), thionyl chloride (0.06 ml, 0.754 mmoles) wasintroduced followed by two drops of dry DMF at 25° C. under anhydrousconditions. After complete conversion of acid to acid chloride,chloroform and thionyl chloride were evaporated under reduced pressureto give yellow colored solid acid chloride, it was flushed with nitrogento remove traces of thionyl chloride and then dissolved in drychloroform (5 ml). 3-amino pyridine (23.67 mg, 0.251mmoles) and triethylamine (0.053 ml) were added to the reaction mixture at 25° C., undernitrogen atmosphere. The reaction mixture was stirred overnight. Thereaction mixture was diluted with chloroform (10 ml) and washed withwater (15 ml) followed by brine (5 ml). The organic layer was dried overanhydrous sodium sulphate and concentrated to give 110 mg of the crudecompound which was purified by column chromatography to yield 87 mg ofthe title compound as a pale yellow colored solid, m.p: 224-228° C.

IR(KBr, cm⁻¹): 711, 795, 1127, 1266, 1255, 1273, 1377, 1403, 1459, 1483,1509, 1573, 1585, 1645, 1740, 2850, 2920, 2955 and 3267.

¹H NMR (300 MHz, DMSO-₆, δ): 3.971 (s, 3H), 5.937 (s, 2H), 7.063-7.094(m, 4H), 7.179-7.205 (d, J=7.8 Hz, 1H), 7.413-7.473 (m, 2H), 7.532-7.560(d, J=8.4 Hz, 1H), 7.709-7.737 (d, J=8.4 Hz, 1H), 8.260-8.336 (m, 3H),8.929 (s, 1H), 10.718(s, 1H).

EXAMPLE 93 N4-(4-pyridyl)-6-chloro-9-(4-fluorobenzyl)-1-methoxy-9H-4-carbazolecarboxamide

To a solution of intermediate 82 (100 mg, 0.251 mmoles) in drychloroform (5 ml), thionyl chloride (0.06 ml, 0.754 mmoles) wasintroduced followed by two drops of dry DMF at 25° C. under anhydrousconditions. After complete conversion of acid to acid chloride,chloroform and thionyl chloride were evaporated under reduced pressureto give a yellow colored solid acid chloride, it was flushed withnitrogen to remove traces of thionyl chloride and then dissolved in drychloroform (5 ml). 4-amino pyridine (23.67 mg, 0.251 mmoles) andtriethyl amine (0.053 ml) was added to the reaction mixture at 25° C.,under nitrogen atmosphere. The reaction mixture was stirred overnight.The reaction mixture was diluted with chloroform (10 ml) and washed withwater (15 ml) followed by brine (5 ml). The organic layer was dried overanhydrous sodium sulphate and concentrated to give 100 mg of the crudecompound which was crystallized from chloroform-pet ether to yield 73 mgof the title compound as a white solid, m.p: 241-245° C.

IR (KBr, cm⁻¹): 757, 779, 798, 818, 1129, 1216, 1253, 1277, 1329, 1411,1459, 1487, 1506, 1585, 1670, 2941, and 3371.

¹H NMR (300 MHz, DMSO-d₆, δ): 3.975 (s, 3H), 5.939 (s, 2H), 7.064-7.095(m, 4H), 7.181-7.209 (d, J=8.4 Hz, 1H), 7.454-7.556 (m, 2H), 7.717-7.807(m, 3H), 8.235 (s,1H), 8.494-8.511 (d, J=5.1 Hz, 2H), 10.882 (s, 1H).

EXAMPLE 94N4-(3,5dichloro-4-pyridyl)-8-chloro-9-cyclohexylmethyl-1-methoxy-9H-4-carbazolecarboxamide

Step 1: Methyl-8-chloro-1-methoxy-9H-4-carbazole carboxylate

To a solution of intermediate 73c (530 mg 1.237 mmoles) in drychloroform (20 mL) thionyl chloride (0.18 mL 2.5009 mmoles), was addedfollowed by a drop of DMF and the reaction mixture was stirred at 25° C.under nitrogen atmosphere for 1 hr, to this added 10 mL methanol andstirred for 10 minutes. Solvent from the reaction mixture was evaporatedunder reduced pressure, diluted with ethyl acetate (100 mL) and washedwith saturated solution of sodium bicarbonate (2×50 mL), with brine(2×50 mL), dried over sodium sulfate and concentrated to give 540 mg ofthe title compound.

¹H NMR (300 MHz, DMSO-d₆, δ):3.937 (s, 3H), 4.073 (s, 3H) 7.13-7.18 (m,2H), 7.48-7.51(m, 1H) 7.856-7.88 (d, J=8.4 Hz, 1H) 8.761-8.789 (d, J=8.4Hz, 1H), 11.78 (s 1H)

Step 2: Methyl-8-chloro-9-cyclohexylmethyl-1-methoxy-9H-4-carbazolecarboxylate

To a suspension of sodium hydride 55% (106.5 mg 2.6632) in dry DMF (5mL), methyl-8-chloro-1-methoxy-9H-4-carboxylate (257 mg 0.8877 mmoles)was added at 0° C. under nitrogen atmosphere and stirred for 1 hr at 25°C. Cooled the reaction mixture to 0° C. and added cycloxylmethyl bromide(0.124 mL 0.8877 mmoles). The reaction mixture was stirred for 2 hrs at25° C. The reaction mixture was quenched with ice cold water (50 mL) andextracted with ethyl acetate (2×30 mL), the organic layer was washedwith water (2×50 mL), brine (2×25 mL), dried over sodium sulfate andconcentrated to give 174 mg of the title compound.

IR (KBR, cm⁻¹): 650, 678, 728, 772, 1026, 1248, 1294, 1571, 1720, 2922and 3425.

¹H NMR (300 MHz, DMSO-d₆, δ): 0.942 (m, 7H) 1.527 (m, 4H), 3.935 (s,3H), 4.058 (s, 3H), 5.008-5.032 (d, J=7.2 Hz, 2H), 7.155-7.207(m, 2H),7.755-7.782 (d, J=8.1 Hz, 1H), 7.503-7.527 (d, J=8.1 Hz, 1H),8.665-8.692 (d, J=8.1 Hz, 1H).

Step 3: 8-Chloro-9-cyclohexylmethyl-1-methoxy-9H-4-carbazole carboxylicacid

To a solution ofmethyl-8-chloro-9-cyclohexylmethyl-1-methoxy-9H-4-carbazole car-boxylate(95 mg 0.2464 mmoles) in 5 mL methanol, 2 mL of 10% sodium hydroxidesolution was added and refluxed for 3 hrs. Methanol from the reactionmixture was evaporated under reduced pressure, diluted with ethylacetate (50 mL) and washed with 10% sodium hydroxide solution (2×20 mL),this aqueous layer was acidified with 1N HCl and extracted with ethylacetate (2×25 mL), dried over sodium sulfate and concentrated to give 90mg of the title compound.

¹H NMR (300 MHz, DMSO-₆, δ): 0.943 (m, 7H), 1.529 (m, 4H), 4.049 (s,3H), 5.006-5.030 (d, J=7.2 Hz, 2H), 7.136-7.195 (t, J=8.8 Hz, 2H)7.479-7.508 (d, J=7.8 Hz, 1H), 7.479-7.508 (d, J=8.1 Hz, 1H),8.824-8.855 (d, J=8.1 Hz, 1H), 12.9 (bs, 1H).

Step 4:4-Nitrophenyl-8-chloro-9-cyclohexylmethyl-1-methoxy-9H-4-carbazolecarboxylate

To a solution of 8-chloro-9-cyclohexylmethyl-1-methoxy-9H-4-carbazolecarboxylicacid (82 mg, 0.2126 mmoles) in 10 mL dry chloroform, thionylchloride (0.047 mL, 1.765 mmoles) was added followed by a drop of DMF.The reaction mixture was stirred for 1 hr at 25° C. under nitrogenatmosphere. To the reaction mixture 4-nitrophenol (29.6 mg, 0.2126mmoles) was added and the reaction mixture was allowed to stirred for 2hrs. The reaction mixture was quenched in ice cold water (50 mL) andextracted with ethyl acetate (2×25 ml). Ethyl acetate layer was washedwith sodium bicarbonate solution (2×20 mL), 1N HCl (2×20 mL) and withbrine (30 mL), dried over sodium sulphate and concentrated to give 50 mgof title compound.

IR(KBR, cm⁻¹): 765, 811, 939, 1209, 1345, 1520, 1590, 1744, 2924, 3434,

¹H NMR (300 MHz, DMSO-d₆, δ): 0.951(m, 7H), 1.531 (m, 4H), 4.057(s, 3H),5.009-5.034 (d, J=7.5 Hz, 2H), 7.156-7.256 (m, 5H), 7.75-7.77 (d, J=8.4Hz, 2H), 8.665-8.694 (d, J=7.8 Hz, 2H)

Step 5: N4-(3,5-dichloro-4-pyridyl)8-chloro-9-cyclohexylmethyl-1-methoxy-9H-4-carboxamide

To a solution of4-nitrophenyl-8-chloro-9-cyclohexylmethyl-1-methoxy-9H-4-carbazolecar-boxylate (44 mg, 0.0919 mmoles) and 3,5-dichloro-4-aminopyridine(21.6 mg, 0.1329 mmoles) in dry DMF (5 ml) at 25° C. under nitrogenatmosphere, sodium hydride 55% (5 mg 0.1195 mmoles) was added andstirred for 1 hr at room temperature. The reaction mixture was quenchedin ice cold water (25 mL) and extracted with ethyl acetate (2×25 mL),ethyl acetate layer was washed with bicarbonate (2×25 mL), with 1N HCl(2×25 mL) and with brine (25 mL), dried over sodium sulphate andconcentrated to give 20 mg of the title compound.

¹H NMR (300 MHz, DMSO-d₆, δ): 0.986-1.016 (m, 7H), 1.55(m, 4H), 4.069(s, 3H) 5.014-5.039(d, J=7.5 Hz, 2H), 7.109-7.619 (m, 2H),7.469-7.492(d, J=6.9 Hz, 1H), 7.591-7.619(d, J=8.4 Hz, 1H),8.316-8.338(d, J=6.6 Hz, 1H), 8.789 (s, 2H), 10.874 (bs, 1H)

EXAMPLE 95N4-(3,5dichloro-4pyridyl)-8-chloro-9-(4-Fluorobenzyl)-1-methoxy-9H-4-carbazolecarboxamide

Step 1: Methyl-8-chloro-9-(4-Fluoro benzyl)-1-methoxy-9H-4-carbazolecarboxylate

To a suspension of sodium hydride 55% (109 mg, 2.76 mmoles) in dry DMF(10 ml), intermediate 73c (265 mg, 0.9153 mmoles) was added at 0° C.under nitrogen atmosphere and stirred for 1 hr at 25° C. Cooled thereaction mixture to 0° C. and 4-fluro benzyl bromide (0.114 mL, 0.915mmoles) was added. The reaction mixture was stirred for 2 hrs at 25° C.,quenched with ice cold water (50 mL) and extracted with ethyl acetate(2×30 mL). The organic layer was washed with water (2×50 mL), brine(2×25 mL), dried over sodium sulfate and concentrated to give 150 mg ofthe title compound.

IR (KBR, cm⁻¹): 637, 729, 773, 872, 1090, 1259, 1295, 1398, 1508, 1706,

¹H NMR (300 MHz, DMSO-d₆, δ): 3.921(s, 3H), 3.940(s, 3H), 6.317(s, 2H),6.886-6.915 (t, J=8.7 Hz, 2H), 6.996-7.055(t, J=8.8 Hz, 2H), 7.144-7.234(m, 2H), 7.492-7.518(d, J=7.8 Hz, 1H) 7.718-7.809 (d J=8.4 Hz, 1H),8.704-8.730 (d, J=7.8 Hz, 1H)

Step 2: 8-Chloro-9-(4-Fluoro benzyl)-1-methoxy-9H-4-carbazole carboxylicacid

To a solution ofmethyl-8-chloro-9-4-Fluorobenzyl)-1-methoxy-9H-4-carbazole car-boxylate(150 mg, 0.377 mmoles) in 10 mL methanol, 2 mL of 10% sodium hydroxidesolution was added and refluxed for 3 hrs. Methanol from the reactionmixture was evaporated under reduced pressure, diluted with ethylacetate (50 mL) and washed with 10% sodium hydroxide solution (2×20 mL),this aqueous layer was acidified with 1N HCl and extracted with ethylacetate (2×30 mL), dried over sodium sulfate and concentrated to give135 mg of the title compound.

IR(KBR, cm⁻¹): 661, 726, 774, 1029, 1128, 1256, 1412, 1510, 1568, 1693,3480.

¹H NMR (300 MHz, DMSO-d₆, δ): 3.914 (s, 3H), 6.316 (s, 2H), 6.889-6.936(t, J=7.0 Hz, 2H), 6.996-7.055 (t, J=8.8 Hz, 2H), 7.123-7.222 (m, 2H),7.477-7.50 (d, J=6.9 Hz, 1H), 7.797-7.825 (d, J=8.4 Hz, 1H), 8.865-8.889(d, J=7.2 Hz, 1H), 12.93 (bs, 1H).

Step 3:4-nitrophenyl-8-chloro-9-(4-Fluorobenzyl-1-methoxy-9H-4-carbazolecarboxylate

To a solution of 8-chloro-9-(4-Fluorobenzyl)-1-methoxy-9H-4-carbazolecarboxylic acid (130 mg, 0.327 mmoles) in 10 mL dry chloroform, thionylchloride (0.071 mL, 0.981 mmoles) was added followed by a drop of DMF.The reaction mixture was stirred for 1 hr at 25° C. under nitrogenatmosphere. To the reaction mixture, 4-nitrophenol (45.5 mg, 0.3272mmoles) was added and the reaction mixture was stirred for 2 hrs. Thereaction mixture was quenched in ice cold water (50 mL) and extractedwith ethyl acetate (2×25 ml). Ethyl acetate layer was washed with sodiumbicarbonate solution (2×25 mL), 1N HCl (2×25 mL) and with brine, driedover sodium sulphate and concentrated to give 150 mg of the titlecompound.

IR(KBR, cm³¹ ¹): 496, 726, 888, 1054, 1081, 1135, 1197, 1347, 1518,1591, 1722,

¹H NMR (300 MHz, DMSO-d₆, δ): 3.926(s, 3H), 6.324(s, 2H), 6.892-6.940(t,J=7.2 Hz, 2H), 7.003-7.061(t, J=8.7 Hz, 2H), 7.149-7.238(m, 2H),7.494-7.532(d, J=7.8 Hz, 1H), 7.778-7.806(d, J=8.4 Hz, 1H)8.711-8.737(d,J=7.8 Hz, 1H).

Step 4:N4-(3,5-dichloro-4-pyridyl)-8-chloro-9-(4Fluorobenzyl)-1-methoxy-9H-4-carbazolecarboxamide

To a solution of4-nitrophenyl-8-chloro-9-(4-Fluorobenzyl)-1-methoxy-9H-4-carbazolecarboxylate (100 mg, 0.1982 mmoles) and 3,5-dichloro 4-amino pyridine(32.3 mg, 0.1982 mmoles) in dry DMF (7 mL), at 25° C. under nitrogenatmosphere, sodium hydride 55% (10.3 mg, 0.2576 mmoles) was added andstirred for 1 hr. The reaction mixtre was quenched in ice cold water (25mL) and extracted with ethyl acetate (2×25 mL). The organic layer waswashed with bicarbonate (2×25 mL), followed by 1N HCl (2×25 mL) and withbrine (25 mL), dried over sodium sulphate and concentrated to give the70 mg of the title compound.

IR(KBR, cm⁻¹): 676, 782, 875, 1032, 1217, 1255, 1400, 1492, 1556, 1668,2926, 3194.

¹H NMR (300 MHz, DMSO-d₆, δ): 3.94(s, 3H), 6.34(s,2H), 6.923-6.970(t,J=8.5 Hz, 2H), 7.024-7.053(t,J=7.4 Hz, 2H), 7.083-7.234(m, 2H),7.463-7.4859 (d,J=6.69 Hz, 1H), 7.622-7.650(d, J=8.4 Hz, 1H),8.345-8.369 (d,J=7.3 Hz, 1H),8.793 (s, 2H), 10.865(s,1H).

EXAMPLE 96N4-(3,5-dichloro-4-pyridyl)-6-chloro-1-methoxy-9-methyl-9H-4-carbazolecarboxamide

Step 1: Methyl-6-chloro-1-methoxy-9-methyl-9H-4-carbazole carboxylate

To a solution of intermediate 73b (400 mg, 1.3817 mmoles) in dry DMF (7mL), sodium hydride 55% (71.8 mg, 1.796 mmoles) was added at 0° C andstirred for 1 hr at 25° C. under nitrogen atmosphere. Methyl iodide(0.17 mL, 2.763 mmoles) was added to the reaction mixture at 0° C. andthe reaction mixture was stirred at 25° C. for 1 hr. Reaction mixturewas quenched with ice cold water (100 mL) and extracted with ethylacetate (2×50 mL), washed with brine (2×50 mL), dried over sodiumsulfate and concentrated to give 400 mg of the title compound.

IR(KBR, cm⁻¹): 625, 849, 1066, 1088, 1250, 1567, 1595, 1712.

¹ H NMR (300 MHz, DMSO-d₆, δ): 3.934(s, 3H), 4.033(s, 3H), 4.150(s, 3H),7.118-7.146(d, J=8.4 Hz, 1H), 7.498-7.534 (dd, J=8.8 Hz, 2H),7.630-7.661(d, J=9.3 Hz, 2H), 8.883-8.889(d, J=1.8 Hz, 1H).

Step 2: 6-Chloro-1-methoxy-9-methyl-9H-4-carbazole carboxylicacid

To a solution of methyl-6-chloro-1-methoxy-9-methyl-9H-4-carbazolecarboxylate (390 mg 1.285 mmoles) in 20 mL methanol, 5 mL of 10% sodiumhydroxide solution was added and stirred for 3 hrs. Methanol from thereaction mixture was evaporated under reduced pressure, diluted withethyl acetate (5 mL) and washed with 10% sodium hydroxide solution (2×2mL). This aqueous layer is acidified with 1N HCl and extracted withethyl acetate (2×25 mL), dried over sodium sulfate and concentrated togive 350 of the title compound

IR(KBR, cm⁻¹): 629, 744, 784, 1017, 1117, 1268, 1449, 1567, 1683, 2942.

¹H NMR (300 MHz, DMSO-d₆, δ): 4.03 (s, 3H), 4.156 (s, 3H), 7.109-7.138(d, J=8.7 Hz, 1H), 7.487-7.524(d, J=9.6 Hz, 1H), 7.625-7.654 (d, J=8.7Hz, 1H), 7.817-7.845(d, J=8.4 Hz, 1H), 8.972-8.979 (d, J=2.1 Hz, 1H)

Step 3: 4-Nitrophenyl-6-chloro-1-methoxy-9-methyl-9H-4-carbazolecarboxylate

To a solution of 6-chloro-1-methoxy-9-methyl-9H-4-carbazole carboxylicacid (350 mg, 1.372 mmoles) in 15 mL dry chloroform, under nitrogenatmosphere, thionyl chloride (0.150 mL, 2.058 mmoles) was added followedby a drop of dry DMF and stirred at 25° C. for 1 hr. To this,4-nitrophenol (190 mg, 1.372 mmoles) was added followed by triethylamine (0.25 mL, 1.784 mmoles) and stirred the reaction mixture for 2 hrat 25° C. Chloroform from the reaction mixture was evaporated anddiluted the residue with ethyl acetate (50 mL). The organic layer waswashed with 1% sodium hydroxide solution (20 mL), 1N HCl (25 mL), brine(50 ML), dried over sodium sulfate and concentrated to give 200 mg ofthe title compound.

IR(KBR, cm⁻¹): 610, 744, 786, 943, 1020, 1048, 1212, 1249, 1306, 1347,1519, 1748,

¹H NMR (300 MHz, DMSO-d₆, δ): 4.107 (s, 3H), 4.211(s, 3H),7.256-7.286(d, J=9 Hz, 1H), 7.537-7.575 (dd, J=8.8 Hz, 1H), 7.692-7.729(m, 3H) 8.208-8.231 (d, J=8.1 Hz, 1H), 8.374-8.405 (d, J=39.3 Hz, 2H),8.868-8.876 (d, J=3 Hz, 1H).

Step 4:N4-(3,5-dichloro-4-pyridyl)-6-chloro-1-methoxy-9-methyl-9H-4-carbazolecarboxamide

To a solution of4-nitrophenyl-6-chloro-1-methoxy-9-methyl-9H-4-carbazole carboxylate(160 mg, 0.4255 mmoles), and 3,5-dichloro-4-amino pyridine (69.36 mg,0.4255 mmoles) in dry DMF (7 mL) at 25° C., sodium hydride 55% (34 mg,0.8510 mmoles) was added and stirred under nitrogen atmosphere for 1 hr.The reaction mixture was quenched in ice cold water (25 mL) andextracted with ethyl acetate (2×25 mL). The organic layer was washedwith bicarbonate (2×25 mL), followed by 1N HCl (2×25 mL) and with brine(25 mL), dried over sodium sulphate and concentrated to give the 90 mgof the title compound.

¹H NMR (300 MHz, DMSO-d₆, δ): 4.046 (s, 3H), 4.172 (s, 3H),7.175-7.203(d, J=8.4 Hz, 1H), 7.5(m, 1H) 7.615-7.667(t, 7.8 Hz, 2H),8.429-8.436 (d, J=2.1 Hz, 1H), 8.758 (s, 2H) 10.769 (s, 1H).

EXAMPLE 97N4-(3,5-dichloro-4-pyridyl-N-oxide)-6-chloro-9-(4-fluorobenzyl)-1-methoxy-9H-4-carbazolecarboxamide

Step 1: 6-Chloro-1-methoxy 9H-4-carbazole carboxylic acid

To a solution of intermediate 73b (400 mg, 1.38 mmoles) in methanol (15ml), an aqueous (5 ml) solution of sodium hydroxide (110 mg, 2.76mmoles) was added and the reaction mixture was refluxed for 6 hours.Methanol was evaporated from the reaction mixture under reducedpressureor, the residue was acidified with 1N HCl and the precipitatedproduct was filtered, washed with water and dried under vacuum, to give380 mg of the title product.

IR(KBR, cm⁻¹): 565, 589, 631, 657, 745, 791, 885, 919, 989, 1015, 1066,1111, 1269, 1291, 1305, 1371, 1418, 1461, 1567, 1613, 1625, 1684, 2623,2849, 2939 and 3461.

¹H NMR (300 MHz, DMSO-₆, δ): 4.065(s, 3H), 7.087-7.115 (d, J=8.4 Hz,1H), 7.399-7.437 (d, J=11.4 Hz, 1H), 7.505-7.534 (d, J=8.7 Hz, 1H),7.5-7.877 (d, J=8.4 Hz, 1H), 8.96-8.967 (d, J=2.4 Hz, 1H),11.84 (s, 1H),12.8 (b s, 1H).

Step 2: 4-Nitrophenyl -6chloro-1-methoxy 9H-4-carbazole carboxylate

To a suspension of 6-chloro-1-methoxy-9H-4-carbazole carboxylic acid(375 mg, 1.36 mmoles) in dry chloroform (15 ml), thionyl chloride (0.3ml, 4.08 mmoles) was added followed by 2 drops of dry DMF and stirredthe reaction mixture under nitrogen atmosphere for two hours. Solventand the excess thionyl chloride were evaporated from the reactionmixture and dried under vacuum. To this residue, dry chloroform (15 ml)was added followed by 4-nitrophenol (190 mg, 1.36 mmoles) andtriethylamine (0.29 ml, 2.04 mmoles) were added and the reaction mixturewas stirred under nitrogen atmosphere for 2 hours. The reaction mixturewas diluted with chloroform (30 ml) and washed with 1N HCl. The organiclayer was washed with brine (20 ml), dried over Na₂SO₄ and concentratedto give 0.38 gm of the title product as a yellow solid.

IR (KBr, cm⁻¹): 3394, 2935, 1746, 1567, 1510, 1347, 1211, 1202, 1100,951 and 745.

¹H NMR (300 MHz, DMSO-₆, δ): 4.13(s, 3H), 7.225-7.255 (d, J=9.0 Hz, 1H),7.438-7.476 (d, J=11.4 Hz, 1H), 7.552-7.581 (d, J=8.7 Hz, 1H),7.679-7.708 (d, J=8.7 Hz, 1H), 8.204-8.231 (d, J=8.1 Hz, 1H),8.364-8.395 (d, J=9.3 Hz, 1H), 8.832-8.839 (d, J=2.1 Hz, 1H),12.06 (s,1H).

Step 3: 4-Nitrophenyl 6-chloro-9-(4-fluoro benzyl)-1-methoxy-4-carbazolecarboxylate

To a solution of 4-Nitrophenyl 6-chloro-9H-4-methoxy-4-carbazolecarboxylate (200 mg, 0.69 mmoles) in dry DMF (10 ml) under nitrogenatmosphere, at 0° C., sodium hydride (60% suspension, 42 mg, 1.036mmoles) was added and the reaction mixture was stirred at roomtemperature for 30 min. The reaction mixture was cooled to 0° C.,4-fluoro benzylbromide (0.086 ml, 0.69 mmoles) was added and stirred thereaction mixture at room temperature for 30 min. The reaction mixturewas diluted with ethyl acetate (25 ml), added 1N HCl (15 ml), shaken andseparated the layers. The aqueous layer was extracted with ethyl acetate(20 ml), combined the organic layers, washed with water (3×15 ml), driedover Na₂SO₄ and concentrated. The crude material was diluted with ethylacetate (20 ml) and allowed to stand at 10° C. for 10 min. The separatedsolid flakes were filtered, washed with pet ether and dried to give 176mg of the title compound.

IR (KBr, cm⁻¹): 2933, 1727, 1567, 1510, 1456, 1342, 1244, 1178, 1130,1042, 1013, 803 and 743.

¹H NMR (300 MHz, DMSO-d₆, δ): 4.031(s, 3H), 5.983 (s, 2H), 7.065-7.089(d, J=7.2 Hz, 4H), 7.2747.303 (d, J=8.7 Hz, 1H), 7.51-7.547 (dd, J=9.0Hz, 1H), 7.693-7.724 (d, J=9.3 Hz, 2H), 7.757-7.786 (d, J=8.7 Hz, 1H),8.228-8.257 (d, J=8.7 Hz, 1H), 8.379-8.408 (d, J=8.7 Hz, 2H),8.886-8.893 (d, J=2.1 Hz, 1H).

Step 4: N4-3,5-dichloro-4-pyridylN-oxide)-6-chloro-9-(4-fluorobenzyl)-1-methoxy-9H-4-carbazolecarboxamide

To a solution of4-nitrophenyl-6-chloro-9-(4-fluorobenzyl)-1-methoxy-9H-4-carbazole-carboxylate(100 mg, 0.198 mmoles) and 3,5 dichloro-4-aminopyridyl N-oxide (35.5 mg,0.198 mmoles) in dry DMF (5 ml), under N₂ atmosphere, 60% sodium hydride(17.29 mg, 0.396 mmoles) was added at 25° C. and the reaction mixturewas stirred overnight. The reaction mixture was poured into ice-coldwater and neutralized with 1N HCl. The compound was extracted withchloroform (3×10 ml), combined the organic layers and washed with water(3×10 ml) and with brine (10 ml). The organic layer was dried overanhydrous sodium sulphate and concentrated to give 110 mg of the crudecompound which was purified by column chromatography to yield 65 mg ofthe title compound as Creamish white solid, m.p: 277-277.5° C.

IR(KBr,cm⁻¹): 524, 764, 792, 832, 1016, 1096, 1132, 1233, 1260, 1308,1422, 1464, 1486, 1509, 1568, 1596, 1647, 2928, 3256 and 3434

¹H NMR (300 MHz, DMSO-d₆, δ): 3.973(s,3H),5.931(s,2H),7.055-7.093(m,3H), 7.185-7.213(d,J=8.4 Hz,1H), 7.436-7.472(dd, J=8.9 Hz,1H),7.615-7.642(d,J=8.1 Hz, 1H), 7.695-7.725(d,J=9 Hz,1H),8.294(s,1H),8.424-8.431(d,J=2.1 Hz,1H),8.763(s,2H), 10.617(s,1H)

EXAMPLE 98N4-(3,5-dichloro-4-pyridyl-N-oxide)-6-chloro-9-(4-methoxybenzyl)-1-methoxy-9H-4-carba-zolecarboxamide

Step 1: 6-Chloro-1-methoxy 9H-4-carbazole carboxylic acid

To a solution of intermediate 73b (400 mg, 1.38 mmoles) in methanol (15ml), an aqueous (5 ml) solution of sodium hydroxide (110 mg, 2.76mmoles) was added and the reaction mixture was refluxed for 6 hours.Methanol was evaporated from the reaction mixture under reducedpressureor, the residue was acidified with 1N HCl and the precipitatedproduct was filtered, washed with water and dried under vacuum, to give380 mg of the title product.

IR(KBR, cm⁻¹: 565, 589, 631, 657, 745, 791, 885, 919, 989, 1015, 1066,1111, 1269, 1291, 1305, 1371, 1418, 1461, 1567, 1613, 1625, 1684, 2623,2849, 2939 and 3461.

¹H NMR (300 MHz, DMSO-d₆, δ): 4.065(s, 3H), 7.087-7.115 (d, J=8.4 Hz,1H), 7.399-7.437 (d, J=11.4 Hz, 1H), 7.505-7.534 (d, J=8.7 Hz, 1H),7.5-7.877 (d, J=8.4 Hz, 1H), 8.96-8.967 (d, J=2.4 Hz, 1H),11.84 (s, 1H),12.8 (b s, 1H).

Step 2: 4-Nitrophenyl-6-chloro-1-methoxy-9H-4-carbazole carboxylate

To a suspension of 6-chloro-1-methoxy-9H-4-carbazole carboxylic acid(375 mg, 1.36 mmoles) in dry chloroform (15 ml), thionyl chloride (0.3ml, 4.08 mmoles) was added followed by 2 drops of dry DMF and stirredthe reaction mixture under nitrogen atmosphere for two hours. Solventand the excess thionyl chloride were evaporated from the reactionmixture and dried under vacuum. To this residue, dry chloroform (15 ml)was added followed by 4-nitrophenol (190 mg, 1.36 mmoles) andtriethylamine (0.29 ml, 2.04 mmoles) were added and the reaction mixturewas stirred under nitrogen atmosphere for 2 hours. The reaction mixturewas diluted with chloroform (30 ml) and washed with 1N HCl. The organiclayer was washed with brine (20 ml), dried over Na₂SO₄ and concentratedto give 0.38 gm of the title product as yellow solid.

IR (KBr, cm⁻¹): 3394, 2935, 1746, 1567, 1510, 1347, 1211, 1202, 1100,951 and 745.

¹H NMR (300 MHz, DMSO-d₆, δ): 4.13(s, 3H), 7.225-7.255 (d, J=9.0 Hz,1H), 7.438-7.476 (d, J=11.4 Hz, 1H), 7.552-7.581 (d, J=8.7 Hz, 1H),7.679-7.708 (d, J=8.7 Hz, 1H), 8.204-8.231 (d, J=8.1 Hz, 1H),8.364-8.395 (d, J=9.3 Hz, 1H), 8.832-8.839 (d, J=2.1 Hz, 1H),12.06 (s,1H).

Step 3: 4-Nitrophenyl 6-chloro-9-(4-methoxybenzyl)-1-methoxy-4-carbazole carboxylate

To a solution of 4-nitrophenyl 6chloro-9H-1-methoxy-4-carbazolecarboxylate (200 mg, 0.69 mmoles) in dry DMF (10 ml) under nitrogenatmosphere, at 0° C., sodium hydride (60% suspension, 42 mg, 1.036mmoles) was added and the reaction mixture was stirred at roomtemperature for 30 min. The reaction mixture was cooled to 0° C.,4-methoxy benzylchloride (0.094 ml, 0.69 mmoles) was added and stirredthe reaction mixture at room temperature for 30 min. The reactionmixture was diluted with ethyl acetate (25 ml), added 1N HCl (15 ml),shaken and separated the layers. The aqueous layer was extracted withethyl acetate (20 ml), combined the organic layers, washed with water(3×15 ml), dried over Na₂SO₄ and concentrated. The crude material wasdiluted with ethyl acetate (20 ml) and allowed to stand at 10° C. for 10min. The separated solid flakes were filtered, washed with pet ether anddried to give 100 mg of the title compound.

IR (KBr, cm⁻¹): 3434, 2837, 1726, 1565, 1523, 1514, 1461, 1353, 1252,1172, 1133, 1040, 1012 and 804.

¹H NMR (300 MHz, DMSO-₆, δ): 3.653 (s, 3H), 4.064(s, 3H), 5.926 (s, 2H),6.774-6.803 (d, J=8.7 Hz, 2H), 6.996-7.026 (d, J=9.0 Hz, 2H),7.281-7.308 (d, J=8.1 Hz, 1H), 7.50-7.536 (dd, J=8.7 Hz, 1H),7.692-7.723 (d, J=9.3 Hz, 2H), 7.752-7.781 (d, J=8.7 Hz, 1H),8.225-8.252 (d, J=8.1 Hz, 1H), 8.377-8.408 (d, J=9.3 Hz, 2H),8.871-8.880 (d, J=2.7 Hz, 1H).

Step 4:N4-(3,5-dichloro-4-pyridyl-N-oxide)-6-chloro-9-(4-methoxybenzyl)-1-methoxy-9H-4-carbazolecarboxamide

To a solution of 4-nitrophenyl6-chloro-9-(4-methoxybenzyl)-1-methoxy-9H-4-carbazolecarboxylate (73 mg,0.141 mmoles) and 3,5 dichloro-4-aminopyridyl N-oxide (25.29 mg, 0.141mmoles) in dry DMF (5 ml), under N₂ atmosphere, 60% sodium hydride(12.33 mg, 0.283 mmoles) was added at 25° C. and the reaction mixturewas stirred overnight. The reaction mixture was poured into ice-coldwater and neutralized with 1N HCl. The compound was extracted withchloroform (3×10 ml), combined the organic layers and washed with water(3×10 ml) and with brine (10 ml). The organic layer was dried overanhydrous sodium sulphate and concentrated to give 70 mg of the crudecompound which was purified by column chromatography to yield 33 mg ofthe title compound as a pale yellow solid, m.p: 247.8-248.5° C.

¹H NMR (300 MHz, DMSO-d₆, δ): 3.641 (s,3H), 4.005 (s,3H),5.873(s,2H),6.762-6.791 (d,J=8.7 Hz,2H), 7.006-7.034(d,J=8.4 Hz,2H), 7.190-7.218(d,J=8.4 Hz,1H), 7.425-7.462 (dd,J=8.9 Hz,1H), 7.608-7.636 (d,J=8.4Hz,1H), 7.690-7.719 (d,J=8.7 Hz,1H), 8.402-8.410 (d,J=2.4 Hz,1H), 8.766(s,2H),10.608(s,1H)

EXAMPLE 99N4-(3,5-dichloro-4-pyridyl-N-oxide)-6-chloro-9-cyclohexylmethyl-1-methoxy-9-H-4-carbazolecarboxamide

Step 1: 6-Chloro-1-methoxy-9H-4-carbazole carboxylic acid

To a solution of intermediate 73b (400 mg, 1.38 mmoles) in methanol (15ml), an aqueous (5 ml) solution of sodium hydroxide (110 mg, 2.76mmoles) was added and the reaction mixture was refluxed for 6 hours.Methanol was evaporated from the reaction mixture under reducedpressureor, the residue was acidified with 1N HCl and the precipitatedproduct was filtered, washed with water and dried under vacuum, to give380 mg of the title product.

IR(KBR, cm⁻¹): 565, 589, 631, 657, 745, 791, 885, 919, 989, 1015, 1066,1111, 1269, 1291, 1305, 1371, 1418, 1461, 1567, 1613, 1625, 1684, 2623,2849, 2939 and 3461.

¹H NMR (300 MHz, DMSO-d₆, δ): 4.065(s, 3H), 7.087-7.115 (d, J=8.4 Hz,1H), 7.399-7.437 (d, J=11.4 Hz, 1H), 7.505-7.534 (d, J=8.7 Hz, 1H),7.5-7.877 (d, J=8.4 Hz, 1H), 8.96-8.967 (d, J=2.4 Hz, 1H),1 1.84 (s,1H), 12.8 (b s, 1H).

Step 2: 4-Nitrophenyl-6-chloro-1-methoxy 9H-4-carbazole carboxylate

To a suspension of 6-chloro-1-methoxy 9H-4-carbazole carboxylic acid(375 mg, 1.36 mmoles) in dry chloroform (15 ml), thionyl chloride (0.3ml, 4.08 mmoles) was added followed by 2 drops of dry DMF and stirredthe reaction mixture under nitrogen atmosphere for two hours. Solventand the excess thionyl chloride were evaporated from the reactionmixture and dried under vacuum. To this residue, dry chloroform (15 ml)was added followed by 4-nitrophenol (190 mg, 1.36 mmoles) andtriethylamine (0.29 ml, 2.04 mmoles) were added and the reaction mixturewas stirred under nitrogen atmosphere for 2 hours. The reaction mixturewas diluted with chloroform (30 ml) and washed with 1N HCl. The organiclayer was washed with brine (20 ml), dried over Na₂SO₄ and concentratedto give 0.38 gm of the title product as a yellow solid.

IR (KBr, cm⁻¹): 3394, 2935, 1746, 1567, 1510, 1347, 1211, 1202, 1100,951 and 745.

¹H NMR (300 MHz, DMSO-₆, δ): 4.13(s, 3H), 7.225-7.255 (d, J=9.0 Hz, 1H),7.438-7.476 (d, J=11.4 Hz, 1H), 7.552-7.581 (d, J=8.7 Hz, 1H),7.679-7.708 (d, J=8.7 Hz, 1H), 8.204-8.231 (d, J=8.1 Hz, 1H),8.364-8.395 (d, J=9.3 Hz, 1H), 8.832-8.839 (d, J=2.1 Hz, 1H),12.06 (s,1H).

Step 3: 4-Nitrophenyl 6-chloro-9-cyclohexylmethyl-1-methoxy-4-carbazolecarboxylate

To a solution of 4-nitrophenyl 6-chloro-9H-1-methoxy-4-carbazolecarboxylate (200 mg, 0.69 mmoles) in dry DMF (10 ml) under nitrogenatmosphere, at 0° C., sodium hydride (60% suspension, 42 mg, 1.036mmoles) was added and the reaction mixture was stirred at roomtemperature for 30 min. The reaction mixture was cooled to 0° C.,cyclohexyl methyl bromide (0.096 ml, 0.69 mmoles) was added and thereaction mixture was stirred at room temperature for 24 hours. Thereaction mixture was diluted with ethyl acetate (25 ml), added 1N HCl(15 ml), shaken and separated the layers. The aqueous layer wasextracted with ethyl acetate (20 ml), combined the organic layers,washed with water (3×15 ml), dried over Na₂SO₄ and concentrated. Thecrude material was purified by column chromatography to give 60 mg ofthe title compound.

¹H NMR (300 MHz, DMSO-d₆, δ): 1.082 (m, 6H), 1.381-1.397 (b, 2H),1.565-1.626 (b, 2H), 1.81 (b, 1H), 4.011(s, 3H), 4.541-4.564 (d, J=6.9Hz, 2H), 7.258-7.286 (d, J=8.4 Hz, 1H), 7.5-7.536 (dd, J=8.7 Hz, 1H),7.682-7.711 (d, J=8.7 Hz, 2H), 7.736-7.767 (d, J=8.7 Hz, 1H), 8.2-8.226(d, J=8.1 Hz, 1H), 8.374-8.403 (d, J=8.7 Hz, 2H), 8.857-8.863 (d, J=1.8Hz, 1H).

Step 4: N4-(3,5-dichloro-4-pyridylN-oxide)-6-chloro-9-cyclohexylmethyl-1-methoxy-9H-4-carbazolecarboxamide

To a solution of4-nitrophenyl-6-chloro-9-cylclohexylmethyl-1-methoxy-9H-4-carbazolecar-boxylate(72 mg, 0.146 mmoles) and 3,5-dichloro-4-aminopyridyl-N-oxide (26.29 mg,0.146 mmoles) in dry DMF (5 ml), under N₂ atmosphere, 60% sodium hydride(12.75 mg, 0.292 mmoles) was added at 25° C. and the reaction mixturewas stirred overnight. The reaction mixture was poured into ice-coldwater and neutralized with 1N HCl. The compound was extracted withchloroform (3×10 ml), combined the organic layers and washed with water(3×10 ml) and with brine (10 ml). The organic layer was dried overanhydrous sodium sulphate and concentrated to give 50 mg of the crudecompound which was purified by column chromatography to yield 38 mg ofthe title compound as a creamish white solid, m.p: 268.8-268.9° C.

IR(KBr,cm⁻¹): 525, 649, 748, 788, 798, 830, 895, 1018, 1096, 1127, 1174,1211, 1234, 1249, 1304, 1422, 1467, 1481, 1529, 1568, 1598, 1662, 852,2926, 3110 and 3310

¹H NMR (300 MHz, DMSO-d₆, δ): 1.074-1.618 (m,11H), 4.045(s,3H),4.497-4.520 (d,J=6.9 Hz,2H), 7.163-7.190 (d,J=8.1 Hz,1H), 7.431-7.467(dd, J=8.7 Hz,1H), 7.579-7.606 (d,J=8.1 Hz,1H), 7.672-7.701 (d,J=8.7Hz,1H), 8.394-8.401 (d, J=2.1 Hz,1H), 8.761 (s,2H), 10.589 (s,1H)

EXAMPLE 100N4-3,5-dichloro-4-pyridyl)-9-methyl-1-methoxy-9H-4-carbazolecarboxamide

Step 1: 1-Methoxy-9-methyl-9H-4-carbazole carbaldehyde

To a suspension of sodium hydride (55% suspension, 0.266 gm, 6.66mnmoles) in dry DMF (15 mL), intermediate 71 (1 gm, 4.44 mmoles) wasadded at 0° C. and stirred for 1 hr at 25° C. The reaction mixture wascooled to 0° C. and added slowly methyl iodide (0.55 mL 8.88 mmoles).This reaction mixture was stirred at 25° C. for 1 hr. The reactionmixture was quenched in ice cold water slowly (100 mL) and extractedwith ethyl acetate (2×50 mL). The organic layer was washed with water(3×50 mL), followed by brine (2×50 mL), dried over sodium sulphate andconcentrated to give 0.875 gm of the title compound.

¹H NMR (300 MHz, DMSO-d₆, δ): 4.095 (s, 3H), 4.187 (s, 3H), 7.284-7.203(m, 2H), 7.8 (t, J=8.0 Hz, 1H), 8.4 (d, 3H), 10.175 (s, 1H)

Step 2: 1-Methoxy-9-methyl-9H-4-carbazole carboxylic acid

To a solution of 1-methoxy-9-methyl 9H-4-carbazolecarbaldehyde (100 mg0.4184 mmoles) in a mixture of 8 mL acetone and 4 mL water, sulfamicacid (48.7 mg 0.502 mmoles) was added followed by a solution of sodiumchlorite (37.8 mg, 0.4184 mmoles) in 2 mL water and the reaction mixturewas stirred at 25° C. for 4 hrs. Acetone from the reaction mixture wasevaporated under reduced pressure, diluted with ethyl acetate 30 mL.Organic layer was separated and basified with freshly prepared sodiumbicarbonate solution and separated the aqueous layer and acidified with1 N HCl and extracted with ethyl acetate (2×25 mL). Ethyl acetate layerwas washed with brine (2×20 mL), dried over sodium sulfate and concertedto give 95 mg of the tide compound.

¹H NMR (300 MHz, DMSO-d₆, δ): 4.028(s,3H), 4.161(s,3H), 7.196-7.070 (m,2H,) 7.632-7.456 (m, 2H), 8.4 (d, 1H), 8.1 (d 1H).

Step 3: 4-Nitrophenyl-1-methoxy-9-methyl-9H-4-carbazole carboxylate

To a solution of 1-methoxy-9methyl 9H-4-carbazolecarboxylic acid (150 mg0.588 mmoles) in 10 mL dry chloroform thionyl chloride (210 mg 1.765mmoles) was added followed by a drop of DMF. The reaction mixture wasstirred for 1 hr at 25° C. under nitrogen atmosphere. To the reactionmixture added 4-nitrophenol (82 mg 0.588 mmoles) followed by triethylamine (77.2 mg 0.764 mmoles) and the reaction mixture was allowed tostirred for 2 hrs. The reaction mixture was quenched in ice cold water50 mL and extracted with ethyl acetate (2×25 ml). Ethyl acetate layerwas washed with sodium bicarbonate solution (2×20 mL), followed by water(1×25 mL), 1 N HCl (2×20 mL) and with brine, dried over sodium sulphateand concentrated to give 100 mg of the title compound.

¹H NMR (300 MHz, DMSO-d₆, δ): 4.09 (s 3H), 4.20 (s 3H), 7.15-7.24 (m2H), 7.50-7.54 (t, J=8.0 Hz, 1H), 7.64-7.71(m 3H), 8.14-8.17 (J=8.7 Hz,1H), 8.36-8.40 (d, J=7.2 Hz, 2H), 8.77-8.79 (d, J=7.8 Hz, 1H).

Step 4: N4-(3,5-dichloro-4-pyridyl)-1-methoxy-9-methyl-9H-4-carbazolecarboxamide

To a solution of 4-nitrophenyl-1-methoxy-9-methyl9H-4-carbazolecarboxylate (50 mg 0.1329 mmoles) and 3,5-dichloro 4-aminopyridine (21.6 mg, 0.1329 mmoles) in dry DMF (5 ml) at 25° C. undernitrogen atmosphere, sodium hydride 55% (7 mg 0.1728 mmoles) was addedand stirred at room temperature for 1 hr. The reaction mixture wasquenched in ice cold water (25 mL) and extracted with ethyl acetate(2×25 mL), ethyl acetate layer was washed with bicarbonate (2×25 mL),with 1N HCl (2×25 mL) and with brine (25 mL), dried over sodium sulphateand concentrated to give 20 mg of the title compound.

¹H NMR (300 MHz, DMSO-d₆, δ): 4.043 (s, 3H), 7.174 (s, 3H), 7.099-7.159(m, 2H) 7.45-7.49 (t, J=7.2 Hz, 1H) 7.568-7.607 (m, 2H) 8.343-8.369 (d,J=7.8 Hz, 1H) 8.77 (s, 2H), 10.699 (s 1H).

EXAMPLE 1013,5Dichloro-4-(4-methoxydibenzo[b,d]-thiophen-1-ylcarboxamido)pyridine

Sodium hydride (0.66 mmols, 36 mg of 50% dispersed in oil) was added toa stirred dry DMF solution of 3,5-dichloro-4-aminopyridine (0.083 g, 0.5mmols) at −10° C. After 30 minutes dry THF (5 ml) solution of the acidchloride of intermediate 86 (0.46 mmols) was added to the reactionmixture at 0° C. The reaction mixture was stirred 3 hrs at roomtemperature and poured in ice-water mixture to get precipitate. Theprecipitated product was filtered, washed with water and dried which wasfurther purified by silica get column chromatography to get white solid.

Yield: 0.078 g, (46%), m.p.: 286-287° C.

IR (KBr, cm−1): 3434, 3192, 2926, 1665, 1567, 1554, 1483, 1287, 1265,1111, 1066, 1016 and 811.84 cm−1.

¹H-NMR: (CDCl₃, 300 MHz, TMS, δ): 4.09 (s, 3H), 6.92 (d, 1H), 7.38 (t,1H), 7.47 (t, 1H), 7.63 (s, 1H), 7.78 (d, 1H), 7.88 (d, 1H), 8.52 (d,1H) and 8.60 (s, 2H).

EXAMPLE 1023,5-Dichloro-4-(4-cyclopentyloxydibenzo[b,d]-thiophen-1-ylcarboxamido)pyridine

Sodium hydride (0.66 mmols, 36 mg of 50% dispersed in oil) was added toa stred dry DMF solution of 3,5-dichloro-4-aminopyridine (0.083 g, 0.5mmols) at −10° C. After 30 minutes dry THF (5 ml) solution of the acidchloride of intermediate 90 (0.25 g, 0.8 mmols) was added to thereaction mixture at 0° C. The reaction mix was stirred 3 hrs at roomtemperature and poured in ice-water mixture to get precipitate. Theprecipitated product was filtered a washed with water and dried whichwas further purified by silica gel column chromatography to yield awhite solid.

yield: 0.16 g ((44%), white solid, m.p.: 285-286° C.

IR (KBr, cm−1): 3433, 3198, 2955, 1665, 1554, 1481, 1441, 1400, 1286,1262, 1167, 1104, 1061, 985, and 820

¹H-NMR: (CDCl₃+ DMSO-d₆, 300 MHz, TMS, δ): 1.60-2.04 (m, 8H), 5.05 (m,1H), 6.90 (d, 1H), 7.20-7.47 (m, 2H), 7.63 (s, 1H), 7.74 (d, 1H), 7.85(d, 1H), 8.50 (d, 1H) and 8.60 (s, 2H).

EXAMPLE 103

N1 (4-methoxyphenyl)-4-methoxydibenzo[b,d]thiophene-1-carboxamide

Sodium hydride (0.66 mmols, 36 mg of 50% dispersed in oil) was added toa stirred dry DMF solution of 4-methoxyaniline (0.1 g, 0.852 mmol) at−10° C. After 30 minutes dry THF (5 ml) solution of the acid chloride ofintermediate 86 (0.2 g, 0.775 mmol) was added to the reaction mixture at0° C. The reaction mixture was stirred 3 hrs at room temperature andpoured in ice-water mixture to get precipitate. The precipitated productwas filtered a washed with water and dried which was further purified bysilica gel column chromatography to yield a white solid.

Yield: 0.18 g (64%), m.p.: 252-253° C.

IR (KBr, cm−1): 3297, 3048, 3012, 2938, 2836, 1644, 1614, 1599, 1555,1568, 1525, 1512, 1439, 1408, 1293, 1262, 1245, 1182, 1173, 1109, 1066,1031, 1016, 821, 789 and 733

¹H-NMR: (CDCl₃, 300 MHz, TMS, δ): 3.8 (s, 3H), 4.05 (s, 3H), 6.80-6.90(fused t, 3H), 7.30(t, 1H), 7.45 (t, 1H), 7.60 (m, 4H0, 7.87 (d,1H) and8.30 (d,1H).

EXAMPLE 104N1-(4-methoxyphenyl)-4-methoxydibenzo[b,d]thiophene-1-carboxamide-5,5-dioxide

To a dichloromethane (10 ml) solution of N1(4-methoxyphenyl)-4-methoxydibenzo-[b,d]thiophene-1-carboxamide (example103), (0.07 g, 0.192 mmols ), 3-chloro-per-benzoic acid (0. 173 g, 0.768mmols, 50% dispersion in water) was added in portions. This reactionmixture was stirred at room temperature for 2 hrs. CH₂Cl₂ was removedfrom reaction mixture and it was triturated with 5% NaHCO₃ solution toget solid product. The product was filtered and washed thoroughly withwater and dried.

Yield: 0.04g (52%), m.p.: 289-290° C.

IR (KBr, cm−1): 3356, 3084, 2926, 2848, 1676, 1599, 1561, 1536, 1509,1497, 1462, 1292, 1254, 1235, 1160, 1136, 1059, 1034, 1013, 926, 871,829, 755, 732, 635 and 624

¹H-NMR: (CDCl₃, 300 MHz, TMS, δ): 3.83 (s, 3H), 4.05 (s, 3H), 6.90-6.99(mixed d, 3H), 7.50-7.58 (m, 3H), 7.61(s, 1H), 7.66 (d, 1H), 7.82 (m,1H), 7.95 (m, 1H).

EXAMPLE 105N1-(4-chlorophenyl)-4-methoxydibenzo[b,d]thiophene-1-carboxamide

Sodium hydride (0.66 mmols, 36 mg of 50% dispersed in oil) was added toa stirred dry DMF solution of 4-chloroaniline (0.11 g, 0.85 mmol) at−10° C. After 30 minutes dry THF (5 ml) solution of the acid chloride ofintermediate 86 (0.2 g, 0.775 mmol) was added to the reaction mixture at0° C. The reaction mixture was stirred 3 hrs at room temperature andpoured in ice-water mixture to get precipitate. The precipitated productwas filtered a washed with water and dried which was further purified bysilica gel column chromatography to yield a white solid.

Yield: 0.07 g (17%), m.p.: 269-270° C.

IR (KBr, cm−1): 3288, 2923, 1651, 1590, 1568,1556, 1514, 1495, 1395,1304, 1288, 1257, 1108, 1064, 1013, 823, 766, and 733.

¹H-NMR: (CDCl₃, 300 MHz, TMS, δ): 4.00 (s, 3H), 6.20 (d, 1H), 7.30(mixed d, 3H), 7.40 (t, 1H), 7.58 (d, 1H), 7.60 (m, 3H), 7.85 (d, 1H),8.25 (d, 1H).

EXAMPLE 106 4-(4-methoxydibenzo[b,d]thiophene-1-ylcarboxamido)pyridine

Sodium hydride (0.66 mmols, 36 mg of 50% dispersed in oil) was added toa stirred dry DMF solution of 4-aminopyridine (0.087 g, 0.92 mmols) at−10° C. After 30 minutes dry THF (5 ml) solution of the acid chloride ofintermediate 86 (0.2 g, 0.775 mmol) was added to the reaction mixture at0° C. The reaction mixture was stirred 3 hrs at room temperature andpoured in ice-water mixture to get a precipitate. The precipitatedproduct was filtered a washed with water and dried which was furtherpurified by silica gel column chromatography to yield a white solid.

Yield: 0.04 g (26%), m.p.: 246-248° C.

IR (KBr, cm−1): 3290, 2925, 1656, 1584, 1567, 1509, 1410, 1330, 1283,1261, 1211, 1109, 1064, 1010, and 816.

¹H-NMR: (CDCl₃, 300 MHz, TMS, δ): 4.07 (s, 3H), 6.91 (d, 1H), 7.36 (t,1H), 7.44 (t, 1H), 7.57-7.63 (mixed d, 3H), 7.85 (s, 1H), 7.89 (d, 1H)8.20 (d, 1H) and 8.56 (d, 1H).

EXAMPLE 1074-(4-Cyclopentyloxydibenzo[b,d]thiophene-1-yl-carboxamido)pyridine

Sodium hydride (0.66 mmols, 36 mg of 50% dispersed in oil) was added toa stirred dry DMF solution of 4-aminopyridine (0.027 g, 0.28 mmols) at−10° C. After 30 minutes dry THF (5 ml) solution of the acid chloride ofintermediate 90 (0.08 g, 0.25 mmols) was added to the reaction mixtureat 0° C. The reaction mixture was stirred 3 hrs at room temperature andpoured in ice-water mixture to get precipitate. The precipitated productwas filtered a washed with water and dried which was further purified bysilica gel column chromatography to yield a white solid.

Yield: 0.025 g (25%), light yellow solid, m.p.: 254-256° C.

IR (KBr, cm−1): 3288, 2958, 1655, 1585, 1565, 1510, 1440, 1415, 1329,1286, 1260, 1166, 1105, 1060, 984, and 823.

¹H-NMR: (CDCl₃, 300 MHz, TMS, δ): 1.70-2.03 (m, 8H), 5.00 (m, 1H), 6.89(d, 1H) 7.34 (t, 1H), 7.44 (t, 1H), 7.55-7.65 (mixed, 3H), 7.85-7.89(mixed, 3H), 8.20 (d, 8.56 (s, 1H).

EXAMPLE 1083,5Dichloro-4-(4-cyclopentyloxydibenzo[b,d]-thiophen-5,5-dioxide-1-ylcarbox-amido)pyridine-N-oxide

To a dichloromethane (10 ml) solution of3,5-dichloro-4-(4-cyclopentyloxy-dibenzo-[b,d]-1-ylcarboxamido)pyridine(example 102) (0.055 g, 0,12 mmols) 3-chloro-per-benzoic acid (0.24mmols, 0.083 g of 50-80% dispersion in water) was added in portions.This reaction mixture was stirred at room temperature for 2 hrs. CH₂Cl₂was removed from reaction mixture and it was triturated with 5% NaHCO₃solution to get solid product The product was filtered and washedthoroughly with water and dried.

Yield: 0.30 g (32%), m.p.: 288° C. (dec.)

IR (KBr, cm−1): 3431, 3099, 2967, 2940, 2872, 1674, 1602, 1565, 1532,1492, 1466, 1449, 1310, 1292, 1266, 1231, 1160, 1137, 1096, 1090, 988,976, 833, and 766

¹H-NMR: (DMSO-d_(6,) 300 MHz, TMS, δ): 1.63-1.96 (m, 811), 5.19 (m, 1H),7.44 (d, 1H), 7.65-7.77 (m, 2H), 7.85 (d, 1H), 7.93 (d, 1H), 8.06 (d,1H), 8.76 (s, 2H) and 11.05 (s, H).

EXAMPLE 1093,5-Dichloro-4-(4-methoxydibenzo[b,d]-thiophen-5,5-dioxide-1-yl-carboxamido)pyridine-N-oxide

To a dichloromethane (10 ml) solution of3,5-Dichloro-4-(4-methoxydibenzo[b,d]-thiophen-1-ylcarboxamido)pyridine(example 102) (0.05 g, 0.12 mmols) 3-chloro-per-benzoic acid (0.24mmols, 0.083 g of 50-80% dispersion in water) was added in portions.This reaction mixture was stirred at room temperature for 2 hrs. CH₂Cl₂was removed from reaction mixture and it was triturated with 5% NaHCO₃solution to get solid product. The product was filtered and washedthoroughly with water and dried.

Yield: 0.02 g (28.2%), m.p.: 243° C. (dec.)

IR (KBr, cm−1): 3399, 3246, 3106, 2925, 1684, 1600, 1564, 1493, 1465,1299, 1268, 1233, 1160, 1136, 1089, 990, 834, 764, 732, 639.

¹H-NMR: (DMSO-d_(6,) 300 MHz, TMS, δ): 4.05 (s, 3H), 7.44 (d, 1H), 7.68(t, 1H), 7.75 (t, 1H), 7.88 (d, 1H), 7.98 (d, 1H), 8.08 (d, 1H), 8.77(s, 2H) and 11.08 (s, 1H).

EXAMPLE 110 3,5Dichloro-4-(4-methoxydibenzo[b,d]-thiophen-5,5dioxide-1-yl-carboxamido)pyridine

Step 1: 4-Methoxydibenzo[b,d]thiophene-1-carboxylic acid-5,5-dioxide

To a solution of intermediate 86 (0.1 g, 0.38 mmols) in dichloromethane(5 ml) was added 3-chloroperbenzoic acid (0.8 mmols, 0.3 g 50-80% inwater) and stirred for 3 hrs at room temperature. Dichloromethane wasremoved and the crude product thus obtained was purified by silica gelcolumn chromatography to get white solid product.

Yield: 0.06 g (54%)

¹H-NMR: (CDCl₃+1 drop DMSO-d₆, 300 MHz, TMS, δ): 3.98 (s, 3H), 6.92 (d,1H) 7.41-7.52 (m, 2H), 7.69 (d, 1H), 7.93 (d, 1H) and 8.42 (d, 1H)

Step 2:3,5-Dichloro-4-(4-methoxydibenzo[b,d]thiophen-5,5-dioxide-1-yl-carboxamido)pyridine

To a solution of the 4-methoxydibenzo[b,d]thiophene-1-carboxylicacid-5,5-dioxide (0.06 g, 0.2 mmols) in dry DMF (2 ml) under N₂atmosphere N,N′-carbonyldiimidazole (0.039 g, 0.24 mmols) was added andthis reaction mixture was stirred for 2 hrs at room temperature. Thisreaction mixture was then added to a stirring solution of4-amino-3,5-dichloropyridine (0.048 g, 0.29 mmols) in dry DMF (2 ml) andNaH (0.29 mmols, 0.021 g of 50% dispersion in oil) at 0° C. After theaddition this reaction mixture was stirred overnight at roomtemperature. The reaction mixture was quenched with water and extractedwith ethyl acetate. Ethyl acetate layer was washed with water, driedover sodium sulphate and contrated to get the crude product which waspurified by silica gel column chromatrography to to white solid product.

Yield: 0.0.27 g (30%), m.p.: 250° C. (dec.)

IR (KBr, cm−1): 3433, 3267, 2927, 1673, 1600, 1553, 1495, 1464, 1400,1305, 1281, 1161, 1138, 1032, 1011, 889, 822, 766, 749, 732

¹H-NMR: (DMSO-d_(6,) 300 MHz, TMS, δ): 4.06 (s, 3H), 7.45 (d, 1H),7.76-7.75 (m, 2H), 7.88 (d, 1H), 7.98 (d, 1H), 8.09 (d, 1H), 8.80 (s,2H) and 11.28 (s, 1H)

EXAMPLE 111 3,5Dichloro-4-(4-difluoromethoxydibenzo[b,d]-thiophen-1-ylcarboxamido)pyridine

To a solution of intermediate 104 (0.1 g, 0.36 mmols) in dry DMF (5 ml)was added 1,1′-carbonyldiimidazole (0.135 g, 0.882 mmols) under N₂atmosphere and reaction mixture was stirred for 2 hrs at roomtemperature. In another flask sodium hydride (1.10 mmols, 0.052 g of 50%dispersion in oil) was added to 3,5-dichloro-4-aminopyridine (0.178 g,1.10 mmols) in dry DMF at room temperature and stirred for 30 minutesunder nitrogen. To this reaction mixture the above imidazoleintermeadiate reaction mixture was added dropwise. After addition thereaction mixture was stirred overnight. The reaction mixture was dilutedwith ethyl acetate and ethyl acetate layer washed with water, brine andconcentrated under vacuo to give the crude product which was purified bycolumn chromatography.

Yield: 0.1 g (85%) white solid, M.P.: 249-251° C.

IR (KBr, cm−1): 3433, 3183, 2927, 1661, 1556, 1499, 1483, 1402, 1386,1286, 1254, 1124, 1091, 1066, 1049, 822, 757 and 715.

¹H-NMR: (CDCl₃, 300 MHz, TMS, δ): 6.74 (t, J=72.6 Hz, 1H), 7.27 (d, 1H),7.41 (t, 1H), 7.50 (t, 1H), 7.72 (fused s, 1H), 7.73 (fused d, 1H), 7.78(fused d, 1H), 8.46 (d, 1H) and 8.60 (s, 2H).

EXAMPLE 112N1-(4-methoxyphenyl)-4-methoxydibenzo[b,d]thiophene-1-sulfonamide

Step 1: 4-Methoxy-dibenzo[b,d]thiophene-1-sulfonic acid

To a chloroform (25 ml) solution of intermediate 84 (0.5 g, 2.33 mmols)was added dropwise chlorosulfonic acid (0.54 g, 4.76 mmols) at −10° C.and the reaction mixture was stirred for 1 hr. The reaction mixture waspoured slowly to crushed ice which gave a precipitate which dissolvedwhen ice melted. The water was evaporated to complete dryness which gavedesired product.

Yield: 0.36 g

¹H-NMR (CD₃OD, 300 MHz, TMS, δ): 4.05 (S, 3H), 7.01 (d, 1H), 7.40 (m,2H), 7.84-7.87 (m, 1H), 8.17 (d, 1H), 9.41-9.44 (m, 1H).

Step 2:N1-(4-methoxyphenyl)-4-methoxydibenzo[b,d]thiophene-1-sulfonamide

To 4-methoxy-dibenzo[b,d]thiophene-1-sulfonic acid (0.1 g, 0.3 mmols)form step 1, was added thionyl chloride (5 ml) and refluxed for 2 hrs.Thionyl chloride was then evaporated and the residue was dissolved indry acetone (20 ml). To the acetone solution 4-aminopyridine (0.044 g,0.36 mmols) followed by pyridine (2 ml) and DMAP (0.005 g) was added.The reaction mixture was allowed to stirred at room temperature for overnight. The reaction mixture was then added to water and extracted withethyl acetate. Ethyl acetate layer on concentration gave crude productwhich was purified over silica gel column chromatography to get pureproduct.

Yield: 0.035 g, of a brownish color solid, m.p.: 158-161° C.

¹H-NMR (CDCl₃, 300 MHz, TMS, δ): 3.65 (s, 3H), 4.05 (s, 3H), 6.57 (d,2H), 6.65 (s, 1H), 6.68 (t, 2H), 6.81 (d, 1H), 7.57 (m, 2H), 7.96 (m,1H), 8.02 (d, 1H), 9.02 (m, 1H).

EXAMPLE 113 2-(4-Methoxydibenzo[b,d]thiophen-1-ylcarboxamido)-pyridine

Sodium hydride (0.66 mmols, 36 mg of 50% dispersed in oil) was added toa stirred dry DMF solution of 2-aminopyridine (0.080 g, 0.92 mmols) at−10° C. After 30 minutes dry THF (5 ml) solution of the acid chloride ofintermediate 86 (0.2 g, 0.77 mmols) was added to the reaction mixture at0° C. The reaction mixture was stirred 3 hrs at room temperature andpoured in ice-water mixture to get precipitate. The precipitated productwas filtered a washed with water and dried which was further purified bysilica gel column chromatography to yield a white solid.

Yield: 0.03 g (19.5%), Yellow solid, m.p.: 182-184° C.

IR (KBr, cm−1): 3401, 3019, 2926, 2400, 1679, 1576, 1513, 1491, 1432,1296, 1259, 1215, 1110, 1066, 1018, 929, 759, 669.

¹H-NMR: (CDCl₃, 300 MHz, TMS, δ): 4.07 (s, 3H), 6.89 (d, 1H), 7.04-7.08(m, 1H), 7.35 (t, 1H), 7.44 (t, 1H), 7.61 (d, 1H), 7.79 (t, 1H), 7.87(d, 1H), 8.13-8.15 (m, 1H), 8.33 (d, 1H), 8.52 (d, 1H) and 8.74 (S, 1H).

EXAMPLE 114 4-(4-Ethoxydibenzo[b,d]thiophen-1-yl-carboxamido)-pyridine

To a solution of intermediate 93 (0.19 g, 0.698 mmols) in dry DMF (5 ml)was added 1,1′-carbonyldiimidazole (0.135 g, 0.882 mmols) under N₂atmosphere and reaction mixture was stirred for 2 hrs at roomtemperature. In another flask sodium hydride (1.10 mmols, 0.052 g of 50%dispersion in oil) was added to 4-amino pyridine (0.1 g, 1.05 mmols) indry DMF at room temperature and stirred for 30 minutes under nitrogen.To this reaction mixture the above imidazole intermeadiate reactionmixture was added dropwise. After addition the reaction mixture wasstirred overnight. The reaction mixture was diluted with ethyl acetateand ethyl acetate layer washed with water, brine and concentrated undervacuo to give the crude product which was purified by columnchromatography.

Yield: 0.075 g, Pale white solid, m.p.: 255° C. (dec.)

IR (KBr, cm−1): 3400, 3040, 2400, 1521, 1474, 1423, 1384, 1215, 1019,929, 759 and 669

¹H-NMR (CDCl₃, 300 MHz, TMS, δ): 1.47 (t, 3H), 4.36 (q, 2H), 6.90 (d,1H), 7.36 (t, 1H), 7.45 (t, 1H), 7.58 (d, 1H), 7.62 (d, 2H), 7.79 (s,1H), 7.89 (d, 1H), 8.21 (d, 1H) and 8.57 (d, 2H).

EXAMPLE 115N1-(4-methoxyphenyl)-8,N8-dimethyl-4-methoxydibenzo[b,d]thiophen-8,1-disulfonamide

Step 1: 4-Methoxy-dibenzo[b,d]thiophene-1,8-disulfonylchloride

To a chloroform (5 ml) solution of intermediate 84 (0.5 g, 2.34 mmols)was added dropwise chlorosulfonic acid (1.36 g, 01.16 mmols) at 0° C.The reaction mixture was stirred 1 hr at room temperature. Chloroformwas evaporated and crushed ice was added to the residue which wasextracted with ethyl acetate. The ethyl acetate layer was washed withwater, brine, dried over Na₂SO₄ which on concentration gave the desiredproduct

Yield: 0.343 g

¹H-NMR (DMSO-d6, 300 MHz, TMS, δ): 4.00 (S, 3H), 7.02 (d, 1H), 7.72 (d,1H), 7.86 (d, 1H), 7.99 (d, 1H), 9.79 (s, 1H),

Step 2: Preparation of6-methoxy-9-(4-methoxyphenylsulfamoyl)dibenzo[b,d]thiophene-2-sulfonylchloride

To a solution of 4-methoxy-dibenzo[b,d]thiophene-1,8-disulfonylchloride(0.2 g, 0.49 mmols) from step 1 in dry acetone (10 ml) was addedp-anisidine (0.6 g, 0.49 mmols) and pyridine (0.06 g, 0.73 mmols). Thereaction mixture was stirred at room temperature for 18 hrs. Acetone wasevaporated and reaction mixture was diluted with water and extracted inethyl acetate. Ethyl acetate layer on concentration gave crude productwhich was purified by silica gel column chromatography to get the pureproduct.

Yield: 0.17 g

¹H-NMR (CDCl₃, 300 MHz, TMS, 5): 3.69 (s, 3H), 4.15 (s, 3H), 6.46 (s,1H), 6.68 (d, 2H), 6.99 (d, 2H), 7.04 (s, 1H), 7.86 (d, H), 7.96 (d,1H), 8.33 (d, 1H) and 9.56 (s, 1H)

Step 3:N1-(4-methoxyphenyl)-N8,N8-dimethyl-4-methoxydibenzo[b,d]thiophene-8,1-disulfonamide

A solution of compound6-methoxy-9-(4-methoxyphenylsulfamoyl)dibenzo[b,d]thiophene-2-sulfonylchloride(0.37 g, 0.074 mmols) from step 2 in dry acetone (10 ml) was addeddimethylammonium hydrochloride (0.028 g, 0.34 mmols) and pyridine (1ml). The reaction mixture was stirred at room temperature over theweeked (36 hrs). Acetone was evaporated and reaction mixture was dilutedwith water and extracted with ethyl acetate. Ethyl acetate layer onconcentration gave crude product which was purified by silica gel columnchromatography to get pure product

Yield: 0.018 g, yellow sticky solid

IR (KBr, cm−1): 3368, 2925, 1606, 1509, 1384, 1153, 1020 and 771

H-NMR (CDCl₃, 300 MHz, TMS, δ): 2.80 (s, 6H), 3.71 (s, 3H), 4.12 (s,3H), 6.54 (s, 1H), 6.71 (d, 2H), 6.98-7.03 (mixed, 3H), 7.65 (dd, 1H),7.86 (d, 1H), 8.30 (d, 1H) and 9.50 (s, 1H)

EXAMPLE 116 3-(4-Methoxydibenzo[b,d]thiophen-1-ylcarboxamido)-pyridine

Sodium hydride (0.66 mmols, 36 mg of 50% dispersed in oil) was added toa stirred dry DMF solution of 3-aminopyridine (0.080 g, 0.92 mmols) at−10° C. After 30 minutes dry THF (5 ml) solution of acid chloride ofintermediate 86 (0.2 g, 0.77 mmols) was added to the reaction mixture at0° C. The reaction mixture was stirred 3 hrs at room temperature andpoured in ice-water mixture to get precipitate. The precipitated productwas filtered a washed with water and dried which was further purified bysilica gel column chromatography to get white solid.

Yield: 0.1 (65%), White solid, m.p.: 243-245° C.

IR (KBr, cm−1): 3271, 3053, 3004, 2938, 1650, 1584, 1567, 1554, 1523,1490, 1439, 1419, 1330, 1285, 1269, 1110,1065, 1014, 879, 799, 785, 766,705.

¹H-NMR: (CDCl₃, 300 MHz, TMS, δ): 4.06 (s, 3H), 6.91 (d, 1), 7.24-7.38(m, 2H), 7.45 (t, 1H), 7.60 (t, 1H), 7.80 (s, 1H), 7.88 (d, 1H), 8.25(d, 1H), 8.41 (d, 2H), and 8.61 (s, 1H)

EXAMPLE 1173,5-Dichloro-4-(6-methyl-4-methoxydibenzo[b,d]-thiophen-1-ylcarboxamido)pyridine

Sodium hydride (0.66 mmols, 36 mg of 50% dispersed in oil) was added toa stirred dry DMF solution of 3,5-4-chloro-4-aminopyridine (0.68 g, 4.2mmols) at −10° C. After 30 minutes dry THF (5 ml) solution of the acidchloride of intermediate 101 (0.28 g, 0.97 mmols) was added to thereaction mixture at 0° C. The reaction mixture was stirred 3 hrs at roomtemperature and poured in ice-water mixture to get precipitate. Theprecipitated product was filtered a washed with water and dried whichwas further purified by silica gel column chromatography to get whitesolid.

Yield: 0.035 g, white solid, m.p.: 259-260° C. (dec.)

¹H-NMR (DMSO-d6, 300 MHz, TMS, δ): 1.34 (t, 3H), 2.91 (q, 2H), 4.15 (s,3H), 7.25 (d, 1H), 7.39-7.43 (m, 2H), 7.76 (d,1H), 8.27 (t, 1H) and 8.80(s, 2H).

EXAMPLE 1183,5,dichloro-4-(4-ethoxy-dibenzo[b,d]thiophen-1-yl-carboxamido)pyridine

To a solution of intermediate 93 (0.2 g, 0.735 mmols) in dry DMF (5 ml)was added 1,1′-carbonyldiimidazole (0.135 g, 0.882 mmols) under N₂atmosphere and reaction mixture was stirred for 2 hrs at roomtemperature. In another flask sodium hydride (1.10 mmols, 0.052 g of 50%dispersion in oil) was added to 3,5-dichloro-4-aminopyridine (0.178 g,1.10 mmols) in dry DMF at room temperature and stirred for 30 minutesunder nitrogen. To this reaction mixture the above imidazoleintermediate reaction mixture was added dropwise. After addition thereaction mixture was stirred overnight. The reaction mixture was dilutedwith ethyl acetate and ethyl acetate layer washed with water, brine andconcentrated under vacuo to give the crude product which was purified bycolumn chromatography.

Yield: 0.04 g, white solid, m.p.: 268-270° C. (dec.)

IR (KBr, cm−1): 3206, 2925, 1666, 1566, 1553, 1484, 1497, 1393, 1285,1262, 1160, 1114, 1064, 770, 715, 753, 642.

¹H-NMR (DMSO, 300 MHz, TMS, δ): 1.53 (t, 31), 4.36 (q, 2H), 7.24 (d,1H), 7.43 (t, 1H), 7.52 (t, 1H), 7.75 (d, 1H), 8.07(d, 1H), 8.41 (d,1H), 8.80 (s, 2H) and 11.01 (s, 1H)

EXAMPLE 1193-(4-Methoxydibenzo[b,d]-thiophene-5,5-dioxide-1-ylcarboxamido)-pyridine

To a solution of3-(4-Methoxydibenzo[b,d]thiophene-1-yl-carboxamido)-pyridine (example116) (0.08 g, 0.238 mmols) in dichloromethane (20 ml) was added3-chloroperbenzoic acid (0.476 mmols, 0.164 g 50-80% in water) andstirred for 3-4 hrs at room temperature. Dichloromethane was removed andresidue was stirred with saturated NaHCO₃ solution (10 ml) for 1 hr andextracted with ethyl acetate which on concentration gave pure product 21as white solid.

Yield: 0.02 g (22%) White solid, m.p.: 241-243° C.

¹H-NMR: (CDCl₃+DMSO, 300 MHz, TMS, δ): 3.92 (s, 3H), 6.93 (d, 1H), 7.09(t, 1H), 7.38-7.41 (m, 2H), 7.54 (d, 1H), 7.58-7.67 (m, 3H), 7.83 (d,1H), 8.79 (S, 1H) AND 10.78 (s, 1H).

EXAMPLE 1203,5-Dichloro-4-(4-benzyloxydibenzo[b,d]-thiophen-1-ylcarboxamido)pyridine

Sodium hydride (0.66 mmols, 36 mg of 50% dispersed in oil) was added toa stirred dry DMF solution of 3,5-dichloro-4-aminopyridine (0.13 g, 0.81mmols) at −10° C. After 30 minutes dry THF (5 ml) solution of the acidchloride of intermediate 96 (0.46 mmols) was added to the reactionmixture at 0° C. The reaction mixture was stirred 3 hrs at roomtemperature and poured in ice-water mixture to get precipitate. Theprecipitated product was filtered a washed with water and dried whichwas further purified by silica gel column chromatography to get whitesolid.

Yield: 0.037 g, off white solid, m.p.: 276° C. (dec.)

IR (KBr, cm−1): 3184, 2922, 2854, 1655, 1556,1498, 1481, 1400, 1364,1289, 1260, 1104, 1061, 1003, 807, 755, 731 1nd 703

¹H-NMR (DMSO, 300 MHz, TMS, δ): 5.48 (s, 2H), 7.32-7.54 (mixed, 8H),7.74 (d, 1H), 8.08 (d, 1H), 8.42 (s, 1H), 8.80 (s, 2H) and 11.03 (s,1H).

EXAMPLE 121N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-(pyrrolidine-2-one-1-yl)-dibenzo[b,d]furan-1-carboxamide

Step 1: N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-(3-chloropropylcarboxamido)dibenzo[b,d]furan-1-carboxamide

N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-amino-dibenzo-[b,d]furan-1-carboxamide(example 59) was dissolved in THF and pyridine (2.0 eq.) and was reactedwith 4-chlorobutyryl chloride (1.2 eq.) at room temperature for 2 h.After the usual workup and purification the product was obtained as awhite solid mp>250° C.

IR (KBr); 3281, 3156, 3035, 2987, 1664, 1650, 1526, 1496, 1381, 1284,1192, 1110, 1080, 914, 814, 677 cm⁻¹.

¹H NMR (300 MHz, DMF-d₇) δ 2.12 (m, 2H), 2.61 (t, 2H), 3.75 (m, 2 H),7.63 (t, J=73.2 Hz, 1 H), 7.64 (d, 1 H), 7.78 (d, 1 H), 8.07 (d, 1 H),8.18 (d, 1 H), 8.65 (s, 1 H), 8.81 (s, 2H), 10.35 (s, 1H).

Step 2: N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-(3-chloropropylcarboxamido)dibenzo[b,d]furan-1-carboxamide

A solution ofN-(3,5-dichloropyrid-4-yl)-4difluoromethoxy-8-(3-chloropropylcarbox-amido)dibenzo[b,d]furan-1-carboxamide (from step 1 as above) inDMF was a suspension of sodium hydride (3 eq.) in DMF and stirred for 1h at room temperature. Workup and purification by silica gel columnchromatography gave the product as a white solid mp: >250° C.

IR(KBr);3212, 2968, 1694, 1673, 1552, 1498, 1474, 1389, 1282, 1204,1130, 1020, 901, 886, 808, 721, 673 cm⁻¹.

¹H NMR (300 MHz, DMF-d₇) δ 2.16 (m, 2H), 2.54 (t, 2H), 3.93 (t, 2 H),7.64 (t, J=73.2 Hz, 1 H), 7.65 (d, 1 H, J=7.8 Hz), 7.87 (d, 1 H, J=9.3Hz), 8.09 (d, 1 H, J=8.1 Hz), 8.20 (dd, 1 H, J=8.7 & 2.4 Hz), 8.58 (d, 1H, J=1.8 Hz), 8.81 (s, 2H), 11.08 (brs, 1H).

The present invention provides a novel series of tricyclic compoundshaving potential therapeutic activity and medical use against severalallergic disorders, particularly in asthma.

In vitro Studies

Inhibition of Phosphodiesterase Enzymes (PDE4)

In this assay, PDE4 enzyme converts [³H] cAMP to the corresponding [³H]5′-AMP in proportion to the amount of PDE4 present The [³H] 5′-AMP thenwas quantitatively converted to free [³H] adenosine and phosphate by theaction of snake venom 5′-nucleotidase. Hence, the amount of [³H]adenosine liberated is proportional to PDE4 activity.

The assay was performed with modification of the method of Thompson andAppleman (Biochemistry; 1971; 10; 311-316) and Schwartz and Passoneau(Proc. Natl. Acad. Sci. U.S.A. 1974; 71; 3844-3848), both referencesincorporated herein by reference in their entirety, at 34° C. In a 200μl total reaction mixture, the reaction mixture contained 12.5 mM ofTris, 5 mM MgCl₂, 1 μM cAMP (cold) and ³H cAMP (0.1 uCi), (Amersham).Stock solutions of the compounds to be investigated were prepared inDMSO in concentrations such that the DMSO content in the test samplesdid not exceed 0.05% by volume to avoid affecting the PDE4 activity.Drug samples were then added in the reaction mixture (25 μl/tube). Theassay was initiated by addition of enzyme mix (75 μl) and the mixturewas incubated for 20 minutes at 34° C. The reaction was stopped byboiling the tubes for 2 mins at 100° C. in a water bath. After coolingon ice for 5 minutes and addition of 50 ug/reaction of 5′-nucleotidasesnake venom from Crotalus atrox incubation was carried out again for 20min. at 34° C. The unreacted substrate was separated from (³H) Adenosineby addition of Dowex AG 1-X8 (Biorad Lab), (400 ul) which wasprequilibrated (1:1:1) in water and ethanol. Reaction mixture was thenthoroughly mixed, placed on ice for 15 minutes, vortexed and centrifugedat 14,000 r.p.m. for 2 mins. After centrifugation, a sample of thesupernatant was taken and added in 24 well optiplates containingScintillant (1 ml) and mixed well. The samples in the plates were thendetermined for radioactivity in a Top Counter and the PDE4 activity wasestimated. PDE4 enzyme was present in quantities that yield <30% totalhydrolysis of substrate (linear assay conditions).

Additionally, activity of the compounds were tested against otherPhosphodiesterase enzymes, namely, PDE 1(Ca.sup.2+/calmodulin-dependent), PDE 2 (cGP-stimulated), PDE 3(cGP-inhibited), PDE 5 (cGP-specific) and PDE 6 (cGP-specific,photoreceptor).

Results were expressed as percent inhibition (IC₅₀) in nMconcentrations. The IC₅₀ values were determined from the concentrationcurves by nonlinear regression analysis.

Cell Based Assay for PDE4 Inhibition:

Method

cAMP elevation studies were conducted in whole U937 cells. U937 cells(ATCC) were grown in RPMI medium containing 10% FBS, 1% pen-strepsolution, 1% L-glutamine for 48 hrs. On the day of assay, the cells werewashed twice with plain RPM1 medium by centrifuging at 800 rpm for 5mins. Cells were resuspended in plain RPM1 medium followed by cellnumber and viability assessment using a trypan blue stain. Cells(0.15-0.2 mio cells per well) were seeded in a 96 well microtitre plateand incubated with various drugs/DMSO vehicle at 37° C. for 15 min. cAMPgeneration was started by addition of 1 μM PGE1 for 15 mins. Theincubation was terminated by addition of cell lysis buffer from cAMPestimation kit. Lysate was used for cAMP quantitatin bychemiluminescence method (DiscoveRX kits). cAMP values were normalizedover PGE1. EC₅₀ values were calculated from dose response curves bynonlinear regression analysis using PRISM software. Sr. No. Example No.IC₅₀(nM) EC₅₀(nM) 1. 1 0.8 83.7 2. 2 0.82 23.8 3. 3 8.68 — 4. 420.18 >300 5. 5 335.60 — 6. 7 26.04 — 7. 9 1.556 17.56 8. 10 1.68 116.99. 11 9.14 >220.1 10. 12 1.21 140 11. 13 2.535 128.0 12. 14 6.41 — 13.15 67.27 — 14. 19 2.535 20.43 15. 20 15.83 — 16. 21 22.6 — 17. 22 105.1— 18. 23 147.3 — 19. 25 110.6 — 20. 27 73.55 — 21. 29 351 — 22. 38 2.8587.94 23. 39 31.74 — 24. 41 0.839 200 25. 42 4.923 44.24 26. 43 61.21 —27. 45 4.54 >300 28. 46 36.84 — 29. 55 1.2 47.51 30. 56 2.851 49.25 31.57 1.735 73.74 32. 58 10.02 147.80 33. 59 4.468 49.22 34. 60 86.42 — 35.68 57.02 36. 79 127.8 — 37. 82 19.61 — 38. 83 5.258 — 39. 84 14.6 — 40.85 8.153 — 41. 86 71.99 — 42. 87 393.0 — 43. 88 128.6 — 44. 93 161.1 —45. 94 281.1 — 46. 95 78.93 — 47. 97 40.28 — 48. 98 39.64 — 49. 99 30.15— 50. 115 37.38 — 51. 121 21.50 —In vivo StudiesInhibition of Serum TNFα Levels in Mice (Graph 1)Treatment

Male Balb/c mice, weighing approximately 20 g, fasted overnight withfree access to water were used for the studies.

Mice were orally dosed with the test compound (10 ml/kg) in appropriatevehicle 30 minutes before LPS injection. Administration of LPS was byIntravenous mode (i.v., 10 ml/kg. Control group of mice received 0.9%saline, while all the treated groups received LPS (0111:B4, 2.5mg/kg).These treated groups then received Roflumilast (0.1 mg/kg),Example-1: 0.05, 0.1, 1 and 3 mg/kg, p.o., (10 ml/kg), per group.

Blood samples were collected from the orbital sinus of treated andcontrol mice 90 mins after LPS was administered. The serum was separatedby centriflgation at 3000.×.g for 5 min, and the serum removed andstored at −20° C. until analysis. Serum levels of TNF alpha weresubsequently measured using a commercially available ELISA kit (Biotrak;Amersham Pharmacia Biotech) following the protocol enclosed in the kit

A 50 μl sample of serum was assayed by ELISA for mouse TNF-.alpha Themean (±SEM) TNF-alpha level from each group was determined and thepercent reduction in TNF levels was calculated. The percent inhibitionof serum TNF-alpha levels caused by the compound was determined relativeto serum TNF-alpha levels in control mice receiving LPS alone.

Inhibition of Arachidonic Acid Induced Ear Edema (Graph 2)

In this in vivo model, the compounds' ability to reduce arachidonic acidinduced edema was compared to the known phosphodiesterase inhibitor,Roflumilast.

Treatment

Albino male Swiss or Balb/c mice, weighing between 20-25 g were used forthe study. Test compounds were administered 30 mins prior to applicationof arachidonic acid (AA). A 2.5% arachidonic acid solution was made inacetone. 20 .mu.l volume of the AA was applied to the left ear of themouse and 20 .mu.l of vehicle (acetone) was applied immediately to theright ear. The mice were sacrificed by CO.sub.2 inhalation 1 hour afterAA. The left and right ears were removed and a 7 mm biopsy was takenfrom each ear and weighed. The difference in biopsy weights between theright and left ear was calculated. Anti-inflammatory effects ofcompounds are evident as an inhibition of the increase in ear weight.

Results are expressed as percent inhibition (ED₅₀) in mglkg. The ED₅₀values were determined from the concentration curves by nonlinearregression analysis and 95% confidence limits were estimatedrespectively.

Results

Inhibition of the PDE4 Activity (in vitro)

The IC₅₀ value for the compound examined was determined fromconcentration-response curves in which varying range of concentrationswere considered as shown in table 1 TABLE 1 IC50 values Compound PDE1PDE2 PDE3 PDE4 PDE5 PDE6 Example-1 44% 69.1 61.8 0.8 4% 36% (100 μM) μMμM nM (100 μM) (100 μM)

1. A compound of general formula (1)

wherein: R¹, R² and R³ may be same or different and are independentlyhydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted cycloalkyl, substituted or unsubstitutedcycloalkylakyl, substituted or unsubstituted cycloalkenyl, substitutedor unsubstituted aryl, substituted or unsubstituted arylalkyl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedheterocyclic ring, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted heteroarylalkyl, —C(O)—R¹, —C(O)O—R¹,—C(O)NR¹R¹, —S(O)_(m)—R¹, —S(O)_(m)—NR¹R¹, nitro, —OH, cyano, amino,formyl, acetyl, halogen, —OR¹, —SR¹, or a protecting group and when twoR² substitutents are ortho to each other, they may be joined to form asaturated or unsaturated cyclic ring, which may optionally include up totwo heteroatoms selected from O, NR¹ or S; is oxygen or sulfur; is aninteger from 0-4; Ar is substituted or unsubstituted aryl, substitutedor unsubstituted arylalkyl, a substituted or unsubstituted heterocyclicring or a substituted or unsubstituted heteroaryl ring; X is oxygen,S(O)_(m) or NR⁵; R⁵ is hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl,substituted or unsubstituted aryl, substituted or unsubstitutedarylalkyl, substituted or unsubstituted heteroaryl, substituted orunsubstituted heterocyclic group, substituted or unsubstitutedheterocyclylalkyl, substituted or unsubstituted heteroarylalkyl,—C(O)—R¹, —C(O)O—R¹, —C(O)NR¹R¹, —S(O)_(m)—R¹, —S(O)_(m)—NR¹R¹, nitro,—OH, cyano, amino, formyl, acetyl, halogen, —OR², —SR² or a protectinggroup; wherein m is 0, 1 or 2; Y is —C(O)NR⁴, —NR⁴SO₂, —SO₂NR⁴ or—NR⁴C(O); R⁴ is hydrogen, substituted or unsubstituted alkyl, hydroxyl,—OR¹, —COOR¹, substituted or unsubstituted aryl, substituted orunsubstituted heterocyclic ring, or an analog, tautomer, regioisomer,stereoisomer, enantiomer, diastereomer, polymorph, pharmaceuticallyacceptable salt, N-oxide, or pharmaceutically acceptable solvatethereof.
 2. A compound according to claim 1 wherein the substituents inthe ‘substituted alkyl’, ‘substituted alkoxy’, ‘substituted alkenyl’,‘substituted alkynyl’, ‘substituted cycloalkyl’, ‘substitutedcycloalkylalkyl’, ‘substituted cyclocalkenyl’, ‘substituted arylalkyl’,‘substituted aryl’, ‘substituted heterocyclic ring’, ‘substitutedheteroaryl ring,’ ‘substituted heteroarylalkyl’, ‘substitutedheterocyclylalkyl ring’, ‘substituted amino’, ‘substitutedalkoxycarbonyl’, ‘substituted cyclic ring’, ‘substituted alkylcarbonyl’,or ‘substituted alkylcarbonyloxy’ may be the same or different and areone or more of hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, oxo,thio, substituted or unsubstituted alkyl, substituted or unsubstitutedalkoxy, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted aryl, substituted orunsubstituted arylalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted cycloalkenyl, substituted or unsubstitutedamino, substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted heterocyclylalkyl ring, substituted orunsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclicring, substituted or unsubstiuted guanidine, —COOR^(x), —C(O)R^(x),—C(S)R^(x), —C(O)NR^(x)R^(y), —C(O)ONR^(x)R^(y), —NR^(x)CONR^(y)R^(z),—N(R^(x))SOR^(y), —N(R^(x))SO₂R^(y), ═N—N(R^(x))(R^(y)),—NR^(x)C(O)OR^(y), —NR^(x)R^(y), —NR^(x)C(O)R^(y)—,—NR^(x)C(S)R^(y)—NR^(x)C(S)NR^(y)R^(z), —SONR^(x)R^(y)—,—SO₂NR^(x)R^(y)—, —OR^(x), —OR^(x)C(O)NR^(y)R^(z), —OR^(x)C(O)OR^(y)—,—OC(O)R^(x), —OC(O)NR^(x)R^(y), —R^(x)NR^(y)C(O)R^(z), —R^(x)OR^(y),—R^(x)C(O)OR^(y), —R^(x)C(O)NR^(y)R^(z), —R^(x)C(O)R^(x),—R^(x)OC(O)R^(y), —SR^(x), —SOR^(x), —SO₂R^(x), or —ONO₂, wherein R^(x),R^(y) and R^(z) are independently hydrogen atom, substituted orunsubstituted alkyl, substituted or unsubstituted alkoxy, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted aryl, substituted or unsubstituted arylalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedcycloalkenyl, substituted or unsubstituted amino, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedheterocyclylalkyl ring substituted or unsubstituted heteroarylalkyl,substituted or an unsubstituted heterocyclic ring.
 3. The compoundaccording to claim 1 wherein R¹ is substituted alkyl.
 4. The compoundaccording to claim 3 wherein R¹ is CHF₂.
 5. The compound according toclaim 1 wherein R¹ is unsubstituted alkyl.
 6. The compound according toclaim 5 wherein R¹ is methyl.
 7. The compound according to claim 1wherein P is O or S.
 8. The compound according to claim 7 wherein P isO.
 9. The compound according to claim 1 wherein R² is substituted alkyl,halogen, cyano, nitro, amino, substituted heterocyclic ring or SO₂NR¹R¹and n=1.
 10. The compound according to claim 9 wherein R² is chloro. 11.The compound according to claim 9 wherein R² is substituted alkyl. 12.The compound according to claim 11 wherein R² is CF₃.
 13. The compoundaccording to claim 9 wherein R² is —NH₂.
 14. The compound according toclaim 9 wherein R² is —SO₂NR¹R¹—.
 15. The compound according to claim 14wherein R² is SO₂N(CH₃)₂.
 16. The compound according to claim 1 whereinY is —C(O)NH—.
 17. The compound according to claim 1 wherein Ar issubstituted or unsubstituted 4-pyridyl; substituted or unsubstituted4-pyridyl-N-oxide; substituted or unsubstituted 3-pyridyl, substitutedor unsubstituted 3-pyridyl-N-oxide; substituted or unsubstituted2-pyridyl; or substituted or unsubstituted 2-pyridyl N-oxide.
 18. Thecompound according to claim 17 wherein said Ar is substituted withhalogen.
 19. The compound according to claim 18 wherein said halogen ischloro.
 20. The compound according to claim 17 wherein Ar is


21. The compound according to claim 20 wherein Ar is

22-59. (canceled)
 60. A process for the preparation of a compound ofgeneral formula (1)

wherein R¹, R² and R³ may be same or different and are independentlyhydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstitued alkynyl, substitutedor unsubstituted cycloalkyl, substituted or unsubstitutedcycloalkylakyl, substituted or unsubstituted cycloalkenyl, substitutedor unsubstituted aryl, substituted or unsubstituted arylalkyl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedheterocyclic group, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted heteroarylalkyl, —C(O)—R¹, —C(O)O—R¹,—C(O)NR¹R¹, —S(O)_(m)—R¹, —S(O)_(m)—NR¹R¹, nitro, —OH, cyano, amino,formyl, acetyl, halogen, —OR¹, —SR¹, or a protecting group and when twoR² substitutents ortho to each other, they may be joined to a form asaturated or unsaturated cyclic ring, which may optionally include up totwo heteroatoms selected from O, NR¹ or S; is oxygen or sulfur; n is aninteger from 0-4; Ar is substituted or unsubstituted aryl, substitutedor unsubstituted arylalkyl, a substituted or unsubstituted heterocyclicring or a substituted or unsubstituted heteroaryl ring; X is oxygen,S(O)_(m) or NR⁵; R⁵ is hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstituedalkynyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl,substituted or unsubstituted aryl, substituted or unsubstitutedarylalkyl, substituted or unsubstituted heteroaryl, substituted orunsubstituted heterocyclic group, substituted or unsubstitutedheterocyclylalkyl, substituted or unsubstituted heteroarylalkyl,—C(O)—R¹, —C(O)O—R¹, —C(O)NR¹R¹, —S(O)_(m)—R¹, —S(O)_(m)—NR¹R¹, nitro,—OH, cyano, amino, formyl, acetyl, halogen, —OR², —SR² or a protectinggroup; m is 0, 1 or2; Y is —SO₂NR⁴; R⁴ is hydrogen, substituted orunsubstituted alkyl, hydroxyl, —OR¹, —COOR¹, substituted orunsubstituted aryl, or a substituted or unsubstituted heterocyclic ring;comprising the steps of (a) reacting the compound of general formula(28) with an amine of the formula ArNHR⁴ to get the novel compounds offormula (1)

and (b) optionally converting the compound of formula 1 into thecorresponding N-oxide.
 61. A method for the preparation of a compound ofgeneral formula (1)

wherein: R¹, R² and R³ may be same or different and are independentlyhydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted cycloalkyl, substituted or unsubstitutedcycloalkylakyl, substituted or unsubstituted cycloalkenyl, substitutedor unsubstituted aryl, substituted or unsubstituted arylalkyl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedheterocyclic group, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted heteroarylalkyl, —C(O)—R¹, —C(O)O—R¹,—C(O)NR¹R¹, —S(O)_(m)—R¹, —S(O)_(m)—NR¹R¹, nitro, —OH, cyano, amino,formyl, acetyl, halogen, —OR¹, —SR¹, or a protecting group and when twoR² substitutents are ortho to each other, they may be joined to a form asaturated or unsaturated cyclic ring, which may optionally include up totwo heteroatoms selected from O, NR¹ or S; P is oxygen or sulfur; n isan integer from 0-4; Ar is substituted or unsubstituted aryl,substituted or unsubstituted arylalkyl, a substituted or unsubstitutedheterocyclic ring or a substituted or unsubstituted heteroaryl ring; Xis oxygen, S(O)_(m) or NR⁵; R⁵ is hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituedalkynyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl,substituted or unsubstituted aryl, substituted or unsubstitutedarylalkyl, substituted or unsubstituted heteroaryl, substituted orunsubstituted heterocyclic group, substituted or unsubstitutedheterocyclylalkyl, substituted or unsubstituted heteroarylalkyl,—C(O)—R¹, —C(O)O—R¹, —C(O)NR¹R¹, —S(O)_(m)—R¹, —S(O)_(m)—NR¹R¹, nitro,—OH, cyano, amino, formyl, acetyl, halogen, —OR², —SR² or a protectinggroup; m is 0, 1 or 2; Y is —C(O)NR⁴, —NR⁴SO₂, —SO₂NR⁴ or —NR⁴C(O); R⁴is hydrogen, substituted or unsubstituted alkyl, hydroxyl, —OR¹, —COOR¹,substituted or unsubstituted aryl, or a substituted or unsubstitutedheterocyclic ring; which comprises the steps of: (a) alkylating acompound of general formula (31)

with an alkylating agent in the presence of a base to yield a compoundthe compounds of general formula (1); and

(b) optionally converting the of formula (1) into the correspondingN-oxide.
 62. A process for the preparation of a compound of generalformula (1)

wherein: R¹, R² and R³ may be same or different and are hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl,substituted or unsubstituted cycloalkenyl, substituted or unsubstitutedaryl, substituted or unsubstituted arylalkyl, substituted orunsubstituted heteroaryl, substituted or unsubstituted heterocyclicgroup, substituted or unsubstituted heterocyclylalkyl, substituted orunsubstituted heteroarylalkyl, —C(O)—R¹, —C(O)O—R¹, —C(O)NR¹R¹,—S(O)_(m)—R¹, —S(O)_(m)—NR¹R¹, nitro, —OH, cyano, amino, formyl, acetyl,halogen, —OR¹, —SR¹, protecting group and when two R² substitutents areortho to each other, they may be joined to a form a saturated orunsaturated cyclic ring, which may optionally include up to twoheteroatoms selected from O, NR¹ or S; P is oxygen or sulfur; n is aninteger from 0-4; Ar is substituted or unsubstituted aryl, substitutedor unsubstituted arylalkyl, a substituted or unsubstituted heterocyclicring or substituted or unsubstituted heteroaryl ring; X is oxygen,S(O)_(m) or NR⁵; R⁵ represents is hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted cycloalkylakyl, substituted orunsubstituted cycloalkenyl, substituted or unsubstituted aryl,substituted or unsubstituted arylalkyl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heterocyclic group, substitutedor unsubstituted heterocyclylalkyl, substituted or unsubstitutedheteroarylalkyl, —C(O)—R¹, —C(O)O—R¹, —C(O)NR¹R¹, —S(O)_(m)—R¹,—S(O)_(m)—NR¹R¹, nitro, —OH, cyano, amino, formyl, acetyl, halogen,—OR², —SR² or a protecting group; m is 0, 1 or2; Y is —NR⁴C(O); R⁴ ishydrogen, substituted or unsubstituted alkyl, hydroxyl, —OR¹, —COOR¹,substituted or unsubstituted aryl, or a substituted or unsubstitutedheterocyclic ring; which comprises the steps of; (a) alkylating acompound of general formula (32)

with an alkylating agent to yield a compound of general formula (1)

(b) optionally converting the compound of formula (1) into thecorresponding N-oxide.
 63. A pharmaceutical composition comprising oneor more compounds according to claim 1 and pharmaceutically acceptablesalts or solvates thereof and one or more pharmaceutically acceptablediluents or carriers.
 64. (canceled)
 65. A method of treating aninflammatory or immune disorder in a subject in need thereof whichcomprises administering to said subject a therapeutically effectiveamount of a compound according to claim
 1. 66. The method according toclaim 65 wherein said inflammatory condition or immune disorder isasthma, bronchial asthma chronic obstructive pulmonary disease, allergicrhinitis, eosinophilic granuloma, nephritis, rheumatoid arthritis,cystic fibrosis, chronic bronchitis, multiple sclerosis, Crohns disease,psoraisis, uticaria, adult vernal cojunctivitis, respiratory distresssyndrome, rhematoid spondylitis, osteoarthritis, gouty arthritis,uveitis, allergic conjunctivitis, inflammatory bowel conditions,ulcerative coalitis, eczema, atopic dermatitis or chronic inflammation.67. The method according to claim 66 wherein said inflammatory conditionis an allergic inflammatory condition.
 68. The method according to claim67 wherein said inflammatory condition or immune disorder is aninflammatory condition or immune disorder of the lungs, joints, eyes,bowels, skin or heart.
 69. The method according to claim 68 wherein saidinflammatory condition is bronchial asthma, nepritis, or allergicrhinitis.
 70. A method for abating inflammation in an affected organ ortissue comprising delivering to said organ or tissue a therapeuticallyeffective amount of a compound according to claim
 1. 71. A method oftreating a disease of the central nervous system in a subject in needthereof which comprises administering to said subject a therapeuticallyeffective amount of a compound according to claim
 1. 72. The methodaccording to claim 71 wherein said disease of the central nervous systemis depression, amnesia, dementia, Alzheimers disease, cardiac failure,shock or cerebrovascular disease.
 73. A method of treating insulinresistant diabetes in a subject in need thereof which comprisesadministering to said subject a therapeutically effective amount of acompound according to claim
 1. 74. A method for the preparation of acompound of general formula (1)

wherein R¹, R² and R³ may be same or different and are hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl,substituted or unsubstituted cycloalkenyl, substituted or unsubstitutedaryl, substituted or unsubstituted arylalkyl, substituted orunsubstituted heteroaryl, substituted or unsubstituted heterocyclicgroup, substituted or unsubstituted heterocyclylalkyl, substituted orunsubstituted heteroarylalkyl, —C(O)—R¹, —C(O)O—R¹, —C(O)NR¹R¹,—S(O)_(m)—R¹, —S(O)_(m)—NR¹R¹, nitro, —OH, cyano, amino, formyl, acetyl,halogen, —OR¹, —SR¹, a protecting group and when two R² substitutentsortho to each other, they may be joined to a form a saturated orunsaturated cyclic ring, which may optionally include up to twoheteroatoms selected from O, NR¹ or S; P is oxygen or sulfur; n is aninteger from 0-4; Ar is substituted or unsubstituted aryl, substitutedor unsubstituted arylalkyl, substituted or unsubstituted heterocyclicring or substituted or unsubstituted heteroaryl ring; X is oxygen,S(O)_(m) or NR⁵; R⁵ represents hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted cycloalkylakyl, substituted orunsubstituted cycloalkenyl, substituted or unsubstituted aryl,substituted or unsubstituted arylalkyl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heterocyclic group, substitutedor unsubstituted heterocyclylalkyl, substituted or unsubstitutedheteroarylalkyl, —C(O)—R¹, —C(O)O—R¹, —C(O)NR¹R¹, —S(O)_(m)—R¹,—S(O)_(m)—NR¹R¹, nitro, —OH, cyano, amino, formyl, acetyl, halogen,—OR², —SR² or a protecting group; m is 0, 1 or 2; Y is —C(O)NR⁴; R⁴ ishydrogen, substituted or unsubstituted alkyl, hydroxyl, —OR¹, —COOR¹,substituted or unsubstituted aryl, or a substituted or unsubstitutedheterocyclic ring, or an N-oxide thereof; comprising the steps of: (a)reacting the compound of formula (11):

with an amine of the formula ArNHR⁴ to yeild a compound of formula (1)

(b) optionally converting the compound of formula (1) into itscorresponding N-oxide.
 75. The method of claim 74 wherein the compoundof formula (11) is formed by (a) converting the compound of generalformula (10)

to general formula (11) wherein FG represents substituted orunsubstituted alkyl, formyl, cyano, halogen, nitro, amino or acarboxylic acid group.
 76. The method of claim 75 wherein the compoundof formula (10) is prepared by: (i) reacting a compound of formula(13.a) with a compound of formula (23) under basic conditions

wherein Z is a halogen; FG is a substituted or unsubstituted alkyl,formyl, cyano, halogen, nitro, or amino; and Hal is halogen, to yield acompound of formula (24)

(ii) cyclizing the compound of general formula (24) under palladiumcatalyzed coupling conditions to form a tricyclic compound of generalformula (10).
 77. The method of claim 75 wherein the compound of formula(10) is prepared by: (i) reacting a compound of general formula (25)with an electrophile

wherein FG is alkyl, formyl, cyano, halogen, nitro, or amino; to yield acompound of formula (10).
 78. The method of claim 75 wherein thecompound of formula (10) is formed by: (i) reacting a compound-ofgeneral-formula (13) with a compound of formula (20) under basicconditions

to yield a compound of general formula (21)

wherein FG is alkyl, formyl, cyano, halogen, nitro, or amino; and Z is ahalogen; and (ii) cyclizing the compound of general formula (21) underacidic conditions followed by oxidation to yeild a tricyclic compound ofgeneral formula (10).
 79. The method of claim 75 wherein the compound offormula (10) is formed by: (i) reacting a compound of formula (16) witha compound of formula (17)

where A is halogen, —OMs, —OTs or —B(OH)₂; Ms is a methanesulfonylgroup; Ts is a p-toluenesulfonyl group; B, is halogen; G is a protectinggroup selected from benzyloxycarbonyl, t-butyloxycarbonyl, isopropyl,cyclopentyl, allyl, acetyl and benzyl, FG is alkyl, formyl, cyano,halogen, nitro, or amino; and Z is halogen; to yield a compound offormula (18)

(ii) deprotecting the compound of formula (18) to yield a compound offormula (19)

(iii) cyclizing the intermediate of formula (19) under basic conditionsto yield a tricyclic compound of formula (10).
 80. The method of claim75 wherein the compound of formula (10) is prepared by: (i) reacting acompound of general formula (12) where Z is a halogen

with an aromatic group of formula (13)

wherein FG is alkyl, formyl, cyano, halogen, nitro, or amino, underbasic conditions to yield a compound of formula (14)

(ii) reducing the compound of formula (14) to obtain a compound offormula (15)

(iii) cyclizing of the compound of formula (15) to yield a tricycliccompound of formula (10).
 81. The method of claim 75, wherein (i) FG ismethyl and step (a) comprises oxidizing the compound of formula (10)with a manganese or chromium reagent to form a compound of formula (11),(ii) FG is cyano and step (a) comprises hydrolyzing the compound offormula (10) to form a compound of formula (11), or (iii) FG is bromineand step (a) comprises reacting the compound of formula (10) withlithium followed by treatment with carbon dioxide to form a compound offormula (11).
 82. The method of claim 74 wherein the compound of formula(11) is prepared by: (a) formylation of a compound of formula (26)

followed by oxidation of the aldehyde group in the resulting compound offormula (27)


83. The method of claim 60, wherein the compound of formula (28) isformed by chlorosulfonylation of the compound of formula (26)


84. The method of claim 61, wherein the compound of formula (31) isprepared by (a) nitrating a compound of formula (26)

to yield a nitro compound of formula (29)

(b) reacting the compound of formula (29) with a reducing agent to yieldan amino compound of general formula (30)

(c) reacting the amino compound of formula (30) with ArSO₂Cl to yield acompound of formula (31)


85. The method of claim 62, wherein the compound of Formula (32) isprepared by: (a) nitrating a compound of formula (26)

to yield a nitro compound of formula (29)

(b) reacting the compound of formula (29) with a reducing agent to yieldan amino compound of formula (30)

(c) reacting the amino compound of formula (30) with ArCOCl or a mixedanhydride of the formula ArCOOCOR⁵ where R⁵ is a substituted orunsubstituted alkyl, cycloalkyl, aryl, heterocyclic ring, heteroaryl, toyield a compound of formula (32)


86. A compound selected from N-(3,5-dichloropyrid-4-yl)-4-methoxydibenzo[b,d]furan-1-carboxamide, N-(3,5-dichloropyrid-4-yl)-4-methoxydibenzo[b,d]furan-1-carboxamide-N1-oxide,N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-nitrodibenzo[b,d]furan-1-carboxamide,N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-amino-dibenzo[b,d]furan-1-carboxamide,or a pharmaceutically acceptable salt thereof.
 87. A compound selectedfrom N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxydibenzo[b,d]furan-1-carboxamide,N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-dibenzo[b,d]furan-1-carboxamide-N-oxide,or a pharmaceutically acceptable salt thereof.
 88. A compound selectedfromN-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-nitro-dibenzo[b,d]furan-1-carboxamide,N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-amino-dibenzo[b,d]furan-1-carboxamide,or a pharmaceutically acceptable salt thereof.
 89. A compound selectedfrom N-(3,5-dichloropyrid-4-yl)-4-isopropyloxydibenzo[b,d]furan-1-carboxamide,N-(3,5-dichloropyrid-4-yl)-4-cyclopropylmethoxydibenzo[b,d]furan-1-carboxamide N-(3,5-dichloropyrid-4-yl)-4-benzyloxydibenzo[b,d]furan-1-carboxamide, or a pharmaceutically acceptable saltthereof.
 90. A compound of claim 1 selected fromN-(pyrid-4-yl)-4-methoxy-dibenzo[b,d]furan-1-carboxamide,N-(pyrid-4-yl)-4-methoxy-dibenzo[b,d]furan-1-carboxamide-N1-oxide,N-(2-chloropyrid-3-yl)-4-methoxy-dibenzo[b,d]furan-1-carboxamide,N-(4-fluorophenyl)-4-methoxy-dibenzo[b,d]furan-1-carboxamide,N-(pyrid-3-yl)-4-methoxy-dibenzo[b,d]furan-1-carboxamide,N-(pyrid-3-yl)-4-methoxy-dibenzo[b,d]furan- 1 -carboxamide-N1-oxide,N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-trifluoromethyldibenzo[b,d]furan-1-carboxamide,N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-trifluoromethyldibenzo[b,d]furan-1-carboxamide-N1-oxide,N-(pyrid-4-yl)-4-methoxy-8-trifluoromethyldibenzo[b,d]furan-1-carboxamide,N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-trifluoromethyldibenzo[b,d]furan-1-carboxamide,N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-trifluoromethyldibenzo[b,d]furan-1-carboxamide-N1-oxide,N-(pyrid-4-yl)-4-difluoromethoxy-8-trifluoromethyldibenzo[b,d]furan-1-carboxamide,N-(pyrid-4-yl)-4-difluoromethoxy-8-trifluoromethyldibenzo[b,d]furan-1-carboxamide-N1-oxide,N-(pyrid-3-yl)-4-difluoromethoxy-8-trifluoromethyldibenzo[b,d]furan-1-carboxamide,N-(pyrid-3-yl)-4-difluoromethoxy-8-trifluoromethyldibenzo[b,d]furan-1-carboxamide-N1-oxide,N-(pyrid-2-yl)-4-difluoromethoxy-8-trifluoromethyldibenzo[b,d]furan-1-carboxamide,N-(pyrid-4-yl)-4-difluoromethoxy-dibenzo[b,d]furan-1-carboxamide,N-(pyrid-4-yl)-4-difluoromethoxy-dibenzo[b,d]furan-1-carboxamide-N1-oxide,N-(pyrid-3-yl)-4-difluoromethoxy-dibenzo[b,d]furan-1-carboxamide,N-(pyrid-3-yl)-4-difluoromethoxy-dibenzo[b,d]furan-1-carboxamide-N1-oxide,N-(5-chloropyrid-2-yl)-4-difluoromethoxy-dibenzo[b,d]furan-1-carboxamide,or a pharmaceutically acceptable salt thereof.
 91. A compound of claim 1selected fromN-(3,5-dichloropyrid-4-yl)-4-cyclopropylmethoxy-dibenzo[b,d]furan-1-carboxamide-N1-oxide,N-(pyrid-4-yl)-4-cyclopropylmethoxy-dibenzo[b,d]furan-1-carboxamide,N-(pyrid-4-yl)-4-cyclopropylmethoxy-dibenzo[b,d]furan-1-carboxamide-N1-oxide,N-(pyrid-3-yl)-4-cyclopropylmethoxy-dibenzo[b,d]furan-1-carboxamide,N-(pyrid-3-yl)-4-cyclopropylmethoxy-dibenzo[b,d]furan-1-carboxamide-N1-oxide,N-(3,5-dichloropyrid-4-yl)-4-hydroxycarbomethoxy-dibenzo[b,d]furan-1-carboxamide,N-(3,5-dichloropyrid-4-yl)-4-isopropyloxy-dibenzo[b,d]furan-1-carboxamide-N1-oxide,N-(pyrid-4-yl)-4-isopropyloxy-dibenzo[b,d]furan-1-carboxamide,N-(pyrid-4-yl)-4-isopropyloxy-dibenzo[b,d]furan-1-carboxamide-N1-oxide,N-(pyrid-3-yl)-4-isopropyloxy-dibenzo[b,d]furan-1-carboxamide,N-(pyrid-3-yl)-4-isopropyloxy-dibenzo[b,d]furan-1-carboxamide-N1-oxide,N-(pyrid-4-yl)-4-methoxy-8-nitro dibenzo[b,d]furan-1-carboxamide,N-(pyrid-3-yl)-4-methoxy-8-nitro dibenzo[b,d]furan-1-carboxamide,N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-chloro-dibenzo[b,d]furan-1-carboxamide,N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-bromo-dibenzo[b,d]furan-1-carboxamide,N-(pyrid-4-yl)-4-methoxy-8-bromo-dibenzo[b,d]furan-1-carboxamide,N-(pyrid-3-yl)-4-methoxy-8-bromo-dibenzo[b,d]furan-1-carboxamide,N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-iodo-dibenzo[b,d]furan-1-carboxamide,N-(pyrid-4-yl)-4-methoxy-8-iodo-dibenzo[b,d]furan-1-carboxamide,N-(pyrid-3-yl)-4-methoxy-8-iodo-dibenzo[b,d]furan-1-carboxamide,N-(4-methylpyrimid-2-yl)-4-methoxy-dibenzo[b,d]furan-1-carboxamide,N-(2,5-dichlorophenyl)-4-methoxy-dibenzo[b,d]furan-1-carboxamide, or apharmaceutically acceptable salt thereof.
 92. A compound of claim 1selected fromN-(3,5-dichloropyrid-4-yl)-4-ethoxycarbomethoxy-dibenzo[b,d]furan-1-carboxamide,N-(3,5-dichloropyrid-4-yl)-4-methoxy-dibenzo[b,d]furan-2-carboxamide,N-(3,5-dichloropyrid-4-yl)-4-methoxy-dibenzo[b,d]furan-3-carboxamide,N4-(4-methoxy-dibenzo[b,d]furan-1-yl)isonicotinamide,N-(3,5-dichloropyrid-4-yl)-4-methoxy-dibenzo[b,d]furan-1-sulfonamide,N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-cyano-dibenzo[b,d]furan-1-carboxamide,3,5-Dichloro-4-(4-ethoxydibenzo[b,d]furan-1-ylcarboxamido)pyridine,N1-Benzyl-4-cyclopentyloxydibenzo[b,d]furan-1-carboxamide,4-(4-Cyclopentyloxydibenzo[b,d]furan-1-ylcarboxamido)pyridine,3,5-Dichloro-4-(4-cyclopentyloxydibenzo[b,d]furan-1-ylcarboxamido)pyridine,4-(4-Methylsulfanyldibenzo[b,d]furan-1-ylcarboxamido)pyridine,N3-(4-Methoxydibenzo[b,d]furan-1-yl)nicotinamide,N1-Benzyl-4-methoxydibenzo[b,d]furan-1-sulfonamide,4-(4-Methoxydibenzo[b,d]furan-1-ylsulfonamido)pyridine,3,5-Dichloro-4-(4-ethoxydibenzo[b,d]furan-1-ylcarboxamido)pyridine-N-oxide,3,5-Dichloro-4-(4-cyclopentyloxydibenzo[b,d]furan-1-ylcarboxamido)pyridine-N-oxide,N-Formyl-1-methoxy-4-[4-methoxyphenylaminosulphonyl]-9H-carbazole,1-methoxy-4-[4-methoxyphenylaminosulphonyl]-9H-carbazole,N-Formyl-1-methoxy-4-[4-methylphenylaminosulphonyl]-9H-carbazole,1-methoxy-4-[4-methylphenylaminosulphonyl]-9H-carbazole,1-methoxy-4-[4-methylphenylaminosulphonyl-N′-methyl]-9H-carbazole,1-methoxy-4-[4-methylphenylaminosulphonyl-N′-methyl]-9methyl carbazole,1-methoxy-4-[4-pyridinylaminosulphonyl]-9H-carbazole, or apharmaceutically acceptable salt thereof.
 93. A compound of claim 1selected fromN4-(2,6-Dichlorophenyl)-1-methoxy-9H-4-carbazolsulphonamide,N4-(2,6-Dichlorophenyl)-9-formyl-1-methoxy-9H-4-carbazolsulphonamide,N4-(4-pyridyl)-1-methoxy-9H-4-carbazole carboxamide,N4-(3,5-dichloro-4-pridyl)-1-methoxy-9H-4-carbazole carboxamide,N4-(3,5-dichloro-4-pyridyl)-6-chloro-1-methoxy-9H-4-carbazolecarboxamide,N4-(3,5-dichloro-4-pyridyl)-9-benzyl-6-chloro-1-methoxy-9H-4-carbazolecarboxamide,N4-(3,5-dichloro-4-pyridyl)-6-chloro-9-cyclohexylmethyl-1-methoxy-9H-4-carbazolecarboxamide,N4-(3,5-dichloro-4-pyridyl)-6-chloro-9-(4-fluorobenzyl)-1-methoxy-9H-4-carbazolecarboxamide,N4-(3,5-dichloro-4-pyridyl)-6-chloro-9-(4-methoxybenzyl)-1-methoxy-9H-4-carbazolecarboxamide,N4-(3,5-dichloro-4-pyridyl)-9-(4-fluorobenzyl)-1-methoxy-9H-4-carbazolecarboxamide, N4-(4-pyridyl)-9-(4-fluorobenzyl)-1-methoxy-9H-4-carbazolecarboxamide,N4-(3,5-dichloro-4-pyridyl)-9-benzyl-1-methoxy-9H-4-carbazolecarboxamide,N4-(3,5-dichloro-4-pyridyl)-9-benzyl-1-ethoxy-9H-4-carbazolecarboxamide,N4-(3,5-dichloro-4-pyridyl)-9-benzyl-6-chloro-1-ethoxy-9H-4-carbazolecarboxamnide,N4-(4-pyridyl)-9-benzyl-1-ethoxy-9H-4-carbazolecarboxamide,N4-(3-pyridyl)-6-chloro-9-(4-fluorobenzyl)-1-methoxy-9H-4-carbazolecarboxamide,N4-(4-pyridyl)-6-chloro-9-(4-fluorobenzyl)-1-methoxy-9H-4-carbazolecarboxamide,N4-(3,5-dichloro-4-pyridyl)8-chloro-9-cyclohexylmethyl-1-methoxy-9H-4-carbazole carboxamide,N4-(3,5-dichloro-4-pyridyl)-8-chloro-9-(4-Fluorobenzyl)-1-methoxy-9H-4-carbazolecarboxamide,N4-(3,5-dichloro-4-pyridyl)-6-chloro-1-methoxy-9-methyl-9H-4-carbazolecarboxamide,N4-(3,5-dichloro-4-pyridyl-N-oxide)-6-chloro-9-(4-fluorobenzyl)-1-methoxy-9H-4-carbazolecarboxamide,N4-(3,5-dichloro-4-pyridyl-N-oxide)-6-chloro-9-(4-methoxybenzyl)-1-methoxy-9H-4-carba-zolecarboxamide,or a pharmaceutically acceptable salt thereof.
 94. A compound of claim 1selected fromN4-(3,5-dichloro-4-pyridyl-N-oxide)-6-chloro-9-cyclohexylmethyl-1-methoxy-9H-4-carbazolecarboxamide,N4-(3,5-dichloro-4-pyridyl)-9-methyl-1-methoxy-9H-4-carbazolecarboxamide,3,5-Dichloro-4-(4-methoxydibenzo[b,d]-thiophen-1-ylcarboxamido)pyridine,3,5-Dichloro-4-(4-cyclopentyloxydibenzo[b,d]-thiophen-1-ylcarboxamido)pyridine,N1 (4-methoxyphenyl)-4-methoxydibenzo[b,d]thiophene-1-carboxamide,N1-(4-methoxyphenyl)-4-methoxydibenzo[b,d]thiophene-1-carboxamide-5,5-dioxide,N1-(4-chlorophenyl)-4-methoxydibenzo[b,d]thiophene-1-carboxamide,4-(4-methoxydibenzo[b,d]thiophene-1-ylcarboxamido)pyridine,4-(4-Cyclopentyloxydibenzo[b,d]thiophene-1-yl-carboxamido)pyridine,3,5-Dichloro-4-(4-cyclopentyloxydibenzo[b,d]-thiophen-5,5-dioxide-1-ylcarbox-amido)pyridine-N-oxide,3,5-Dichloro-4-(4-methoxydibenzo[b,d]-thiophen-5,5-dioxide-1-yl-carboxamido)pyridine-N-oxide,3,5Dichloro-4-(4-methoxydibenzo[b,d]-thiophen-5,5-dioxide-1-yl-carboxamido)pyridine,3,5Dichloro-4-(4-difluoromethoxydibenzo[b,d]-thiophen-1-ylcarboxamido)pyridine,N1-(4-methoxyphenyl)-4-methoxydibenzo[b,d]thiophene-1-sulfonamide,2-(4-Methoxydibenzo[b,d]thiophen-1-ylcarboxamido)-pyridine,4-(4-Ethoxydibenzo[b,d]thiophen-1-yl-carboxamido)-pyridine,N1-(4-methoxyphenyl)-8,N8-dimethyl-4-methoxydibenzo[b,d]thiophen-8,1-disulfo-amide,3-(4-Methoxydibenzo[b,d]thiophen-1-ylcarboxamido)-pyridine,3,5-Dichloro-4-(6-ethyl-4-methoxydibenzo[b,d]-thiophen-1-ylcarboxamido)pyridine,3,5,dichloro-4-(4-ethoxy-dibenzo[b,d]thiophen-1-yl-carboxamido)pyridine,3-(4-Methoxydibenzo[b,d]-thiophene-5,5-dioxide-1-ylcarboxamido)-pyridine,3,5-Dichloro-4-(4-benzyloxydibenzo[b,d]-thiophen-1-ylcarboxamido)pyridine,N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-(pyrrolidine-2-one-1-yl)-dibenzo[b,d]furan-1-carboxamide,or a pharmaceutically acceptable salt thereof.
 95. A compound selectedfrom